3-(2-pyrrolidinyl)-indoles and method of preparation



United States Patent 3,361,759 3-(Z-PYRROLIDINYD-INDOLES AND METHOD OF PREPARATION William C. Anthony and Jacob Szmuszkovicz, Kalamazoo, Mich, assignors to The Upjohn Company, Kalamazoo,

MiclL, a corporation of Delaware No Drawing. Filed Oct. 7, 1963, Ser. No. 314,502 14 Claims. (Cl. 260-32614) The present invention relates to novel 3-(2-pyrrolidinyl) indoles, 3-(2-pyrrolidinylidene)-3H-indoles, 3-(1- pyrrolin-2-yl)indoles, and more particularly relates to novel 3-(2-pyrrolidinyl)indole free bases, acid addition salts, quaternary ammonium salts, and N-oxides; 3-(2- pyrrolidinylidene)-3H-indole free bases, acid addition salts, and quaternary ammonium salts; and 3-(1pyrrolin 2-yl)indole free bases; to novel compositions containing said novel 3-(2-pyrrolidinyl)indoles as active ingredients, and to a novel process for preparing 3-(2-pyrrolidinyl) indoles and 3-(2-piperidyl)indoles. This application is a continuation-in-part of application Ser. No. 166,926, filed Jan. 17, 1962, now abandoned.

The novel 3-(2-pyrrolidinyl)indole free bases as Well as the 3-(2-piperidyl)indole free bases of the present invention can be represented by the formulae:

in which formulae R and R represent hydrogen and alkyl of l to 4 carbon atoms, inclusive; R and R represent hydrogen, alkyl of 1 to 4 carbon atoms, inclusive, halogen, e.g., chloro, bromo, and fluoro, alkoxy of 1 to 4 carbon atoms, inclusive, e.g., methoxy, ethoxy, propoxy, butoxy, and the like, benzyloxy, p-alkoxybenzyloxy of 8 to 11 carbon atoms, inclusive, e.g., p-methoxybenzyloxy, p-ethoxybenzyloxy, p-propoxybenzyloxy, pbutoxybenzyloxy, and the like, hydroxy, nitro, and amino; R represents alkyl of 1 to 4 carbon atoms, inclusive, benzyl, and p-alkoxybenzyl of 8 to 11 carbon atoms, inclusive, with the proviso that when at least one of R and R is bydroxy, then R represents alkyl; R represents hydrogen, benzyl, p-alkoxybenzyl of 8 to 11 carbon atoms, inclusive, and alkyl of 1 to 4 carbon atoms, inclusive, with the proviso that when at least one of R and R is hydroxy, then R only represents hydrogen and alkyl; and R represents hydrogen and alkyl of 1 to 4 carbon atoms, inclusive. Representative alkyl radicals of 1 to 4 carbon atoms, inclusive, are, e.g., methyl, ethyl, propyl, butyl, isopropyl, isobutyl, and the like. Representative p-alkoxybenzyl radicals of 8 to 11 carbon atoms, inclusive, are, e.g., p-methoxybenzyl, p-ethoxybenzyl, p-propoxybenzyl, p-butoxybenzyl, and the like.

The compounds of the present invention can be prepared by the following processes:

(A) 3-(2-pyrrolidinyl)indoles having the formula:

wherein R, R R R R and R have the above values, can be prepared by heating a Z-pyrrolidone having the formula:

III

wherein R, R and R have the above values, with an indole having the formula:

wherein R has the above value and R and R represent the same values as R and R above with the exclusion of hydroxy, in thepresence of phosphorus oxychloride at a temperature between about 50 and about 150 C. for a period between about 1 to about 10 hours to produce a 3-(2-pyrrolidinylidene)-3H-indole havin the formula:

wherein R, R R R R and R have the above values, and reducing the 3-(2-pyrrolidinylidene)-3H-indole with a reducing agent.

The preferred reaction temperature for the preparation of the 3-(2-pyrrolidinylidene)-3H-indoles is within the range of about to about C. Advantageously the reactants are admixed at a temperature of about 20 C. or less, external cooling being applied Where necessary; and, when the admixture is complete, the temperature of the reaction mixture is raised to the above-indicated level. Although the reactants can be mixed in any order in the preliminary stage, it is preferred that the phosphorus oxychloride is first added to the 2-pyrrolidone and that to this mixture is then added the starting indole in solution in a further quantity of the 2-pyrrolidone, the temperature being maintained at or below 20 C. throughout the mixing operations.

While the relative molecular proportions of the components of the reaction mixture can vary over a wide range, it is advantageous that the phosphorus oxychloride be employed in an amount which is in excess of that which would represent an equimolar amount with respect to the starting indole. The proportion of 2-pyrrolidone is preferably greatly in excess of that which would represent equimolar proportions with respect to both the phosphorus oxychloride and the indole. The excess of 2- pyrrolidone serves as a convenient solevnt medium for the reaction. If desired, however, and especially where the 2-pyrrolidone is a solid, there can also be present in the reaction mixture an insert solvent such as dioxane, tetrahydrofuran, and the like.

Reduction of the 3-(Q-pyrrolidinylidene)-3H-indoles can be accomplished by utilizing metal hydrides, such as lithium aluminum hydride, lithium borohydride, sodium borohydride, with sodium borohydride being preferred;

or the reduction can be accomplished by Catalytic hydrogenation utilizing a noble metal catalyst, e.g., platinum oxide, palladium-black, palladium-charcoal, or the like; or the reduction can be accomplished with an alkali metal (e.g., sodium, lithium or potassium) and a lower alkanol (e.g., methanol, ethanol, propanolor butanol). The reduction with metal hydrides is preferably conducted in an inert solvent, such as tetrahydrofuran, diisopropyl ether, diethyl ether, N-methylmorpholine, dioxane, and the like; in the case of sodium borohydride, the inert solvent can also be a lower alkanol, ethanol being preferred. In many instances, the reduction is conveniently carried out at the boiling point of the solvent used, although other temperatures between about zero and 100 C. can be employed.

The catalytic hydrogenation is usually carried out in the presence of methanol, although other solvents such as ethanol, benzene, or ethyl acetate can also be employed. The reduction is preferably conducted at about 25 C.

For best results, the choice of reducing agent is important in the above process as well as the processes hereinafter disclosed depending on the R, R R and R substituents. When R or R is benzyl or p-alkoxybenzyl, the reduction should be carried out with a metal hydride or t'catalytically with a platinum catalyst, e.g., plantinum oxide, in order to avoid debenzylation which results with the use of a palladium catalyst. Similar precautions should be taken when it is desired to produce a 4-, 5-, 6-, and 7-benzyloxy or p-alkoxybenzyloxy substituted compound unless it is desired to produced a 4-, 5-, 6-, or 7- hydroxy substituted compounds whereupon the reduction can be carried out with a palladium catalyst.

When a 4-, 5-, 6-, or 7-nitro substituted compound is desired, the reduction should be carried out with sodium borohydride in order to retain the nitro substituents. If it is desired to convert the nitro radical to an amino radical, then reduction can be carried out with lithium aluminum hydride or catalytically. Alternatively, the amino substituted 3-(2-pyrrolidinyl)indoles can be produced by utilizing an amino substituted starting indole (Formula IV; R or R is amino).

3-(2-piperidyl)indoles having the formula:

R2 GR]. R; N R4 wherein R, R R R R and R have the above values can also be produced by the above process utilizing a 2- piperidone having the formula:

IIIA

wherein R, R and R have the above values in lieu of a 2-pyrrolidone (Formula III).

(B) 3-(2-pyrrolidinyl)indoles having the formula:

Fil {W R N mwlj wherein R, R R R R and R have the above values and-R represents alkyl of 1 to 4 carbon atoms, inclusive,

benzyl, orp-alkoxybenzyl of 8 to 11 carbon atoms, in-

clusive, with the proviso that when at least one of R and R represents hydroxy, then R isralkyl, can be prepared by heating phosphorus oxychloride, a 2-pyrrolidone (Formula III) and an indole having the formula:

N is

VII

wherein R R R and R have the above values, utilizing the same reaction conditions as set forth in Process A, and reducing the resulting product catalytically or with a metal hydride as discussed above.

3-(2-piperidyl)indoles having the formula:

ll \NRsR wherein R, R R R R R and R have the above values, can also be produced by the above process utilizing a Z-piperidone (Formula 'IIIA) in lieu of a 2-pyrrolidone (Formula III).

3-(2-pyrrolidinyl)indoles of Formula VI, wherein R is alkyl, benzyl, or p-alkoxybenzyl and the corresponding 3-(2-pipe1idyl)indoles, can also be prepared by the addition of an alkyl, benzyl, 0r p-alkoxybenzyl radical to 3- (2-pyrrolidinyl)indoles of Formula H, and the corresponding 3-(2-piperidyl)indoles, by reaction with an alkyl, benzyl, or p-alkoxybenzyl halide in the presence of an alkaline condensing agent such as alkali-metal amides or alkali-metal hydrides.

(C) 3-(2-pyrrolidinyl)indoles having the formula:

V III wherein R R R and R have the above values, and wherein R and R taken individually represent hydrogen, aryl, aralkyl, and alkyl, and R and R taken together with N also represent a saturated heterocyclic amino radical, with a nitroalkane having the formula;

wherein R and R have the above values, to produce a 3-(4-nitrobutyryl)indole having the formula:

X11 wherein R R R and R have the above values, and R and R represent the same values as R and R above with the exclusion of nitro and hydroxy, reducing the thus-produced 3-(l-pyrrolin-2-yl)indole with a metal hydride or by catalytic hydrogenation in the presence of a noble catalyst as set forth more fully in Process A, above, to produce a 3-(2-pyrrolidinyD-indole having the formula:

R] N R 3 R1 XIII wherein R R R R R and R have the above values, and alkylating or benzylating the pyrrolidinyl nitrogen of the thus-produced product. The alkylation or benzylation of the pyrrolidinyl nitrogen can be conveniently accomplished by reacting a compound of Formula XIII with an alkyl, benzyl, or p-alkoxybenzyl halide, e.g., methyl iodide, ethyl bromide, isopropyl iodide, butyl iodide, isobutyl bromide, benzyl iodide, benzyl chloride, p-methoxybenzyl chloride, p-ethoxybenzyl iodide, pbutoxybenzyl bromide, p-propoxybenzyl iodide, and the like. Alternatively, the alkylation or benzylation of the pyrrolidinyl nitrogen can be accomplished by reacting a compound of Formula XIII with an alkanoic or a benzoic anhydride to produce a 3-(1-acyl-2-pyrrolidinyl) indole having the formula:

k n N R R, l-X 1 pyrrolidinyl nitrogen of a compound of Formula XIII wherein at least one of R and R is hydrogen, can be accomplished by reacting the said compound with an alkyl formate (e.g., methyl formate, ethyl formate, and the like), and reducing the resulting N-formyl compound with a metal hydride, preferably lithium aluminum hydride.

(D) 3-(2-pyrrolidinyl)indoles of Formula VIII can also be prepared by reducing and concomitantly cyclizing with hydrogen and Raney nickel a 3-(4-nitrobutyryl)indole having the formula:

XIV

wherein R R R R and R have the above values,

to produce a 3 (1 pyrrolin 2 yl) indole having the formula:

wherein R R R R and R have the above values, alkylating or benzylating the pyrrolidinyl nitrogen of the resulting cyclized compound with an alkyl, benzyl, or p-alkoxybenzyl halide to obtain a 3-(2-pyrrolidinylidene)-3H-indole, and either (1) reducing the 3-(2-pyrrolidinylidene)-3H)-indole with a metal hydride, preferably sodium borohydride, to produce a compound of Formula VIII (R =hydrogen) or (2) alkylating or benzylating the 3-(2-pyrrolidinylidene)-3H-indole with an alkyl, benzyl, or p-alkoxybenzyl halide to produce a 3-(2-pyrrolidinylidene)-3H-indole quaternary ammoni um salt having the formula:

wherein R, R R R R R and R have the above values and Y is halogen, and reducing the quaternary ammonium salt With a metal hydride, preferably sodium borohydride, to produce a compound of Formula VIII (R =alkyl, benzyl, or p-alkoxybenzyl).

(E) 3-(2-pyrrolidinyl)indoles having the formula:

wherein R, R R R R R and R have the above values, can be prepared by reacting a 3-indolyl 2-aminoethyl ketone quaternary ammonium salt' (U.S. Patent 3,037,991) having the formula:

fate, a para-toluene-sulfonate anion, e.g., that derived from methyl para-toluene-sulfonate, and the like, with an alkali metal cyanide to produce a 3-(3-cyanopropionyl) indole having the formula:

wherein R R R R R and R have the above values, reducing and cyclizing the 3-(3-cyanopropionyl) indole utilizing hydrogen and Raney nickel catalyst to produce a 3-(l-pyrrolin2-yl)indole having the formula:

RZTRI R14 X3 315 wherein R R R R R and R have the above values, catalytically hydrogenating the 3-(1-pyrrolin-2- yl)indole or reducing with a metal hydride as set forth more fully in Process A, above, to produce a 3-(l-pyrrolidinyl)indole having the formula:

R1 \N/ R13 I H T A a XXI XXI with an alkanoic or a benzoic anhydride to produce a 3-(l-acyl-2-pyrrolidinyl)indole having the formula:

wherein R R R R R R and X have the above values and reducing the resulting N-alkanoyl or N-benzoyl compound with a metal hydride, preferably lithium aluminum hydride as more fully set forth in Process C.

Alternatively, 3-(1-pyrro1in 2 yl)indoles within the scope of Formula XX and having the formula:

wherein R R R R and R have the above values, can 'be converted to compounds within the scope of Formula VI by reacting with an alkyl halide, a benzyl halide, or a p-alkoxybenzyl halide to produce a 3-(2-pyrrolidinylidene)-3H-indole acid addition salt having the formula:

R14 I I R XXIV wherein R, R R R R and R have the above values and X is halogen, and reducing the acid addition salt with a metal hydride.

(F) 3-(2-pyrrolidinyl)indoles of Formula I can also be prepared by reacting an indole magnesium iodide with a 2-pyrrolidone (Formula III) and reducing with sodium in n-butanol by utilizing the reaction conditions disclosed by Akkerman et al., Rec. Trav. Chim. 73, 629, 1954, for the preparation of the corresponding 3-(2-piperidyl) indoles.

Acid addition salts of the present invention can be prepared from the 3(2-pyrrolidinyl)indole free bases (Formula I) and 3-(2-pyrrolidinylidene)-3H-indole free bases (Formula V) by conventional methods. For example, the free base can be dissolved in an aqueous solution of the appropriate acid and the salt can be isolated by evaporation of the solution. Alternatively, the free base dissolved in an organic solvent such as methanol, ethanol, isopro panol, ethyl acetate, ether, and the like, can be treated with the appropriate acid and according to the nature of the solvent employed the desired salt will separate spontaneously or can be precipitated by the addition of a solvent in which the salt is insoluble. Suitable acids include hydrochloric, sulfuric, 'hydriodic, hydrobromic, phosphoric, tartaric, acetic, citric, succin-ic, lactic, maleic, benzoi, salicylic, and the like.

3-(2-pyrrolidinyl)indole quaternary ammonium salts can be prepared by reacting 3-(2-pyrrolidinyl)indole free basses in an inert solvent with a quaternary ammonium salt-forming compound such as methyl iodide, ehtyl bromide, octyl bromide, benzyl chloride, dimethyl sulfate, methyl para-toluenesulfonate, and the like.

The 3-(2-pyrrolidinyl)indole N-oxides can be prepared by reacting 3-(2-pyrrolidinyl)indole free bases with an oxidizing agent such as hydrogen peroxide, peracetic acid, m-chloroperbenzoic acid, and the like.

Starting indoles utilized in the above-outlined processes can be prepared by known procedures. Such methods, including the welhknown Fischer synthesis, are summarized in Chemistry of Carbon Compounds, edited by E. H. Rodd, vol. IVA, pages 71-77, Elsevier, New York, 1957; and Heterocyclic Compounds, Elderfield, vol. 3, 1952, John Wiley and Sons, Inc. Representative starting indoles include indole, l-ethylindole, 7-ethylindole, 1- methylindole, 4-, 5-, 6- and 7-methylindoles, S-ethylindole, 6-butylindole, S-isobutylindole, 1,4-dimethylindole, 4,6- dimethylindole, 1,7-dimethylindole, 1,7-dipropylindole, 1,5-dipropylindole, 1,6-dibutylindole, l-benzylindole, 4,5- dipropylindole, 5,7-dimethylindo1e, 4,6-diethylindole, 1- propyl-6-ethylindole, l-benzyl-S-methylindole, l-benzyl- S-ethylindole, 4-rnethyl-7-isopropylindole, 1-butyl-4-methyl-7-isopropylindole, S-choroindoe, S-bromoindole, 5- methoxyindole, S-fluoroindole, 5-benzyloxyindole, 6-benzyloxyindole, Z-methylindole, l-methyl-S-ethoxyindole, 1- methyl-S-methoxyindole, 2-methyl-5,7-dichloroindole, 5 ,6- dimethoxyindole, Z-ethylindole, l-ethyl-2-methylindole, Z-t-butylindole, 2-propylindole, 2,4,7-trimethylindole, 6- aminoindole, l-methyl 5,6 dimethoxyindole, Z-methyl- 5,6-dirnethoxyindole, 2-methyl-5-fluoroindole, Z-rnethyl- S-methoxyindole, Z-methyl-S-chloroindole, 2-rnethyl-7- nitroindole, 2-methyl-5-benzyloxyindole, 2-propyl-5-benzyloxyindole, and the like.

The starting Z-pyrrolidones can be prepared by reacting an alkylamine with a gamma-butyrolactone as disclosed by Adams et al., J. Amer. Chem. Soc. 63, 228, 1941. An alternative procedure involves reacting a 2-pyrrolidone, unsubstituted in the 1-position, with an alkylhalide in the presence of an alkaline condensing agent such as alkalimetal amides, alkali-metal hydrides, or alkali-metal alkoxides. Representative 2-pyrrolidones which can be prepared by the above procedures and utilized herein include l-methyl-Z-pyrrolidone, l-butyl-Z-pyrrolidone,

1,3 -dirnethyl-2-pyrrolidone, 1,4-dimethyl-2-pyrrolidone, 1,S-dimethyl-Lpyrrolidone, l-methyl-5-ethyl-2-pyrrolidone, l-ethyl-Z-pyrrolidone, l-propyl-Z-pyrrolidone,

l-butyl-3 -propyl-2-pyrrolidone,

1, 3-diethyl-2-pyrrolidone, 1,4-diethyl-Z-pyrrolidone, 1,4-dipropyl-2-pyrrolidone,

1,5 -dibutyl-2-pyrrolidone,

,3,5-trimethyl-2-pyrrolid one, ,4,S-trimethyl-2-pyrrolidone, ,3,3-trirnethyl-Z-pyrrolidone, 1,5,5-trimethyl-2-pyrrolidone, 1-ethyl-3-propy1-2pyrrolidone, l-ethyl-4propyl-2-pyrrolidone, 1-propyl-4-isopropyl-2-pyrrolidone, l,3,3-triethyl-2-pyrrolidone 1,3 ,4-triethyl-Z-pyrrolidone, l,4-diethyl-3-methyl-2-pyrrolidone, 1,4-diethyl-4-methyl-2 pyrrolidone, 1-ethyl5-methyl-2-pyrrolidone, l-methyl-4,4-diethyl-2-pyrrolidone, 1-butyl-3,3-diethyl-2-pyrrolidone, l-ethyl-4-rnethyl-2-pyrrolidone, 1-methyl-5-butyl-2-pyrrolidone, l-methyl-5-ethyl-2-pyrrolidone,

and the like.

The starting Z-piperidones can be prepared by substituting a delta-valerolactone for a gamma-butyrolactone utilized in preparing Z-pyrrolidones as noted above. The 2-piperidones can also be prepared by reducing a l-substituted Z-pyridone, e.g., by catalytic reduction in the presence of a platinum oxide catalyst as disclosed by Leonard et al., J. Amer. Chem. Soc. 71, 3098, 1949. An alternative procedure involves reacting a 2-piperidone, unsubstituted in the 1-position, with an alkyl halide in the presence of an alkaline condensing agent such as alkali-metal amides, alkali-metal hydrides or alkali-metal alkoxides. Representative 2-piperidones which can be prepared by the above procedures and utilized herein include l-methyl-Z-piperidone,

1-ethyl-2-piperidone,

1-propyl-2-piper-idone,

1-isopropyl-2-piperidone,

l-buty1-2-piperidone,

1,3-dimethyl-2-piperidone,

l,6-dimethyl-21piperidone,

l,3,3-trimethyl-2-piperidone, 1-methyl-6-ethyl-2-piperidone, l-methyl-5-ethyl-2-piperidone 1-methyl-6-propyl-2-piperidone, l-methyl-6-butyl-2-piperidone, 1-methyl-3-ethyl-2-piperidone, 1-methyl-4,S-diethyl-Z-piperidone,

1,3 ,5 -trirnethyl-2-piperidone,

1,4,4-trimethyl-2-piperidone, 1-methyl-5-butyl-5-ethyl-2-piperidone, l-methyl-6-isopropyl-Z-piperidone, 1,4-dimethyl2-piperidone,

1,5,6-trimethyl-2-piperidone, 1,6-dimethyl-5-ethyl-2-piperidone, 1,S-dimethyl-Z-piperidone, 1-methyl-5isopropyl-2apiperidone,

and the like.

The 3-indolyl Z-aminoethyl ketones utilized in Process C can be prepared by the process set forth in J. Amer. Chem. Soc. 82, 1180, 1960.

- The following examples are illustrative of the products and processes of the present invention but are not to be construed as limiting.

EXAMPLE l.3 1 -METHYL-2-PYRROLIDINYL) INDOLE FREE BASE A. 3- (1-methyZ-Z-pyrrolidinylidene) -3H-indole Phosphorus oxychloride (40.8 g.; 0.26 mole) was added to 40 ml. (0.4 mole) of l-methyl-Z-pyrrolidone at such a rate that the temperature of the mixture did not exceed 15 C. The mixture was stirred for 20 minutes and a solution of 28.0 g. (0.24 mole) of indole and 40 ml. (0.4 mole) of l-methyl-Z-pyrrolidone was slowly added. The resulting mixture was then carefully heated to 35 C. The mixture was quickly immersed in an ice bath when the temperature began to rise. The temperature rose to C. When the temperature dropped to 70 C., the mixture was heated at 80 C. for two hours, cooled and mixed with ice water. When the solution was clear, 42.0 g. of sodium hydroxide was added. The mixture was filtered and the solid material was washed with water. The solid was dissolved in 200 ml. of ethanol, the mixture was filtered, and the filtrate was diluted at its boiling point with 300 ml. of water. After cooling for 1 hour, 41.6 g. (89% yield) of 3-(1-methyl-Z-pyrrolidinylidene)-3H-indole was obtained, which product melted between 229-231 C.

Analysis.Calcd. for C H N C, 78.75; H, 7.12; N, 14.13. Found: C, 78.35; H, 7.18; N, 14.43.

B. 3-(1-methyl-Z-pyrrolidinyl)indole free base 9.8 g. (0.05 mole) of 3-(1-methyl-2-pyrrolidinylidene)- 3H-indole was added to a refluxing mixture or" 4.5 g. (0.12 mole) of lithium aluminum hydride and ml. of tetrahydrofuran. The mixture was refluxed for 6 hours, cooled, decomposed with water in tetrahydrofuran, followed by approximately 10 ml. of concentrated sodium hydroxide solution. Ether was added and the mixture was filtered.

The solid was washed with ethenThe filtrates were combined, dried over anhydrous potassium carbonate, filtered and concentrated. The oily residue was recrystallized from Skellysolve B (Skellysolve B is essentially a mixture of hexanes having a boiling range of 140-160 F.) to yield 7.5 g. (75% yield) of 3-(l-methyl-2-pyrrolidinyl)indole free base which melted between 9597 C.

Analysis..-Calcd. for C H N C, 77.96; H, 8.05; N, 13.99. Found: C, 77.58; H, 8.31; N, 13.89.

A mixture of 4.8 g. (0.025 mole) of 3-(1-methyl-2-pyrrolidinylidene)-3H-indole, 100 ml. of absolute methanol, and 0.2 g. of platinum oxide was shaken with hydrogen at 50 pounds initial pressure for 20 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in boiling Skellysolve B and filtered through glass wool. The solution was put in an ice bath for 30 minutes and the resulting crystals were recovered by filtration, to yield 4.1 g. (80% yield) of 3-(1-methyl-2- pyrrolidinyl)indole free base.

EXAMPLE 2.l -METHYL-3 l-METHYL-Z-PYR- ROLIDINYL) INDOLE A. 1-met-hyl-3-(1-methyl-2-pyrrolidinyl)ina'oZe free base A solution of 3-(l-methyl-Z-pyrrolidinyl)indole (25 g.; 0.125 mole) in 100 ml. of ether was added with stirring during 20 min. to a suspension of sodium amide (0.128 mole) in 475 ml. of liquid ammonia. Methyl iodide (18.0 g.; 0.128 mole) was then added during 30 min. The mixture was stirred for 30 min. Ammonia was then allowed to evaporate, 100 ml. of 'Water was aded, and the mixture was extracted with ether. The extracts were washed with saturated salt solution, dried over sodium sulfate, and evaporated to give an oil (20 g.). Distillation of this oil (19 g.) at 0.01 mm. afforded 12.52 g. of 1-methyl-3-(1- methyl-Z-pyrrolidinyl)indole free base (49% yield), with a boiling point of 113 C. The oil crystallized on standing in the cold for a few days and melted between 45.5- 47.5 C.

Analysing-Calm. for C H N C, 78.46; H, 8.47; N, 13.07. Found: C, 77.96; H, 8.98; N, 13.05.

B. 1-methyl-3-(1-methyl-Z-pyrfolidinyl) indole picrate 1-methyl-3-(1-methyl-2 pyrrolidinyl)indole free base (0.119 g.; 0.56 millimole) in ml. of ethanol was treated with 7.6 ml. of saturated ethanolic picric acid solution. Crystallization commenced after a few seconds; 0.217 g. of 1-methyl-3-(1-methyl-2-pyrrolidinyl)indole picrate melting between 196196.5 C. was obtained. On recrystallization from ethanol the compoundrnelted between 196.5- 197 C.

Analysis.Calcd. for C20H21N50'1: C, H, N, 15.80. Found: C, 53.93; H, 4.41; N, 15.85.

EXAMPLE 3.3-( 1,5 -DIMETHYL-2-PYRROL- IDINYLHNDOLE FREE BASE A. 3-(4-nitrovaleryl)indole A mixture of 3-dimethylamino-1-(3-indolyl)-1-propanone (21.6 g.; 0.1 mole), 100 ml. of nitroethane, and sodium methoxide (0.54 g.; 0.01 mole) was stirred and refluxed for 6 hours while a low stream of nitrogen was passed through the suspension. After standing for 12 hours the mixture was filtered. The solid thus obtained was washed with ether and then with water. The washed solid Was crystallized from isopropyl alcohol. The product, 3-(4- nitrovaleryDindole, weighed 11.61 g. (47% yield) and melted between 155156 C.

Analysis.-Calcd. for C H N O C, 63.40; H, 5.73; N, 11.38. Found: C, 63.42; H, 5.64; N, 10.98.

B. 3-(S-meflryl-l-pyrrolin-2-yl)indole A solution of 3-(4-nitrovaleryl)iudole (36.9 g.; 0.15 mole) in 300 ml. of absolute ethanol was hydrogenated at50 lbs. (initial pressure of hydrogen) in the presence of 2 teaspoons of Raney nickel catalyst. The theoretical amount of hydrogen was absorbed in 18 hours. The mixture was filtered and evaporated. The residue was recrystallized from isopropyl alcohol. The recrystallized product, 3-(5-rnethyl-l-pyrrolin 2 yl)indole, weighed 16.1 g. and melted between 196197 C. and a second crop of 6.8 g. melted between 194-196 C. The total yield was 77% of theoretical.

Ultraviolet spectrum (ethanol) showed k 218 (25,- 300); sh 238; 256 (11,750); 271 (9,800); 291 (11,900); sh 301.5: sh 320 (2,750; sh 332 (2,200).

Analysis.-Calcd. for C H H C, 78.75; H, 7.12;. N,

14.13. Found: C, 78.77; H, 6.90; N, 14.41.

C. 3-(S-meIhyZ-Z-pyrrolidinyl)indole hydrochloride A solution of 9.4 g. of 3-(5-methyl-l-pyrrolin-2-yl)indole in 300 ml. of ethanol was hydrogenated in the presence of platinum oxide catalyst (05 g.) at initial pressure of 50 lbs. After the theoretical amount of hydrogen had been absorbed, the mixture was filtered and the resulting solution was evaporated to about 25 ml. and acidified with ethereal hydrogen chloride. Ether was then added until crystallization began. Three recrystallizations of the resulting solid from ethanol produced 9.1 g. (81.4% yield) of 3-(S-methyl-Z-pyrrolidinyl)indole hydrochloride which melted between 225226 C.

Analysis.Calcd. for C H ClN C, 65.95; H, 7.24; N, 11.84; Cl, 14.97. Found: C, 65.94; H, 7.10; N, 11.70; Cl, 14.94.

D. 3-(1,5-dimethyl-2-pyrr0lidinyl)indole free base (1) By lithium aluminumhydride reducti0n.l.2 g. (0.005 mole) of 3-(5-rnethyl-2-pyrrolidinyl)indole hydrochloride was dissolved in 10 ml. of water. The solution was basified with 15% aqueous sodium hydroxide solution and extracted with ether. The extracts were washed with saturated salt solution, dried over anhydrous sodium sulfate, and evaporated to give 1 g. of 3-(5-met hyl-2-pyrrolidinyl)indole free base as a yellow oil. Methyl formate (50 ml.) was added to the oil. The solution was refluxed for 93 hours and then evaporated to dryness to give 3-(1- formyl-5-methyl-2-pyrrolidinyl)indole as an amorphous solid. The solid was dissolved in benzene, the solution was dried by distillation, and was added to a solution of lithium aluminum hydride (1.2 g.) in ml. of ether. After refluxing for 18 hours, the mixture was decomposed in succession with 1.2 ml. of water, 1.2 ml. of 15% aqueous sodium hydroxide solution, and 3.6 ml. of water. The suspension was filtered, the solid was washed with ether, and the filtrate was evaporated to give 1.11 g. of oily crystals. Three recrystallizations from ether-Skellysolve B produced 0.182 g. (17% yield) of 3-(1,5-dimethyl-2-pyrrolidinyl)indole free base with a melting point between l45148 C.

(2) By sodium borohydride reducti0n.--A solution of 3-(5-methyl-l-pyrrolin-Z-yl)indole (1.98 g.; 0.01 mole) in 15 ml. of methanol and 5 ml. of methyl iodide was refluxed for 3 hours. The solution was then evaporated to dryness and the resulting solid, 3-(1,5-dimethyl-2-pyrrolidinylidene)-3H-ind0le hydroiodide, crystallized from methanol-ether; 1.7 g., M.P. 224227 C. Two crystallizations raised the M.P. to 237239.5 C.

Ultraviolet spectrum (ethanol) showed A sh 246 (11,200); 251 (13,500); 265 (10,050); 271 (10,400); 332 (18,700).

Analysis.Calcd. for C H IN C, 49.42; H, 5.04; I, 37.30; N, 8.24. Found: C, 49.49; H, 4.98; I, 37.11; N, 8.62.

Sodium borohydride (1.3 g.) was added to a suspension of 3-(1,5-dimethyl-2-pyrrolidinylidene)-3H-indole hydroiodide (1.3 g.; 3.83 millimoles) in 100 ml. of ethanol. The mixture was stirred for 4 hours and then evaporated to dryness. Water (100 ml.) and 20% aqueous sodium hydroxide solution (10 ml.) was added and the mixture was extracted with ether. The extract was washed with water, dried with sodium sulfate, and evaporated to give 0.8 g. of crude product. Two crystallizations from methanol-ether afforded colorless prisms of 3-(1,5-dimethyl-2- pyrrolidinyl)indole free base, M.P. 151152 C.

Ultraviolet spectrum (ethanol) showed 217 (37,- 750); sh 274 (5,950); 280 (6,350); 289 (5,250).

Analysis.Calcd. for C H N C, 78.46; H, 8.47; N, 13.07. Found: C, 78.36; H, 8.45; N, 13.07.

Ultraviolet and infrared spectra showed this compound to be identical with that obtained above by reducing 3- (1-formyl-5-methyl-2-pyrrolidinyl)indole with lithium aluminum hydride.

EXAMPLE 4.-METHYL-3 l-METHYL-LPYR- ROLIDINYLHNDOLE FREE BASE A. 5 -methyl-3- (1 methyl-2-pyrr0iidinylidene)- SH-indole Phosphorus oxychloride (40.8 g.; 0.26 mole) was added with stirring over a period of 30 minutes to 40 ml. (0.4 mole) of l-methyl-Z-pyrrolidone cooled in an ice bath. The temperature was not permitted to exceed 15 C. The thick yellow paste was stirred while cooling in the ice bath for an additional 20 minutes. To the mixture was added with stirring during 15 minutes a solution of 10.1 g. (0.77 mole) of S-methylindole in 40 ml. (0.4 mole) of l-methyl- 2-pyrrolidone. The temperature did not rise above 8 C. The ice bath was removed. In sixteen minutes a maximum temperature of 49 C. was reached and a solid precipitated. The mixture was heated at 80 C. for 2 hours. After cooling, the mixture was dissolved in 500 ml. of water. The solution was made basic by the addition of a solution of 60 g. of sodium hydroxide in 300 ml. of water. The resulting paste was filtered and the solid was washed with 300 ml. of water and then dissolved in 250 ml. of ethanol. The volume was reduced to 125 ml. and 60 ml. of water was added while the solution was kept boiling. The solution was cooled to produce 15.3 g. (93.5% yield) of 5-methy1-3-(1-methyl-Z-pyrrolidinylidene)-3H indole which sintered at 202 C. and melted between 209212 C. (dec.).

AnaZysis.Calcd. for C H N C, 79.21; H, 7.60; N, 13.20. Found: C, 78.87; H, 7.64; N, 12.94.

B. 5-methyl-3-(1-methyl-Z-pyrrolidinyl)indole free base A mixture of 12.7 g. of 5-methyl-3-(l-methyLZ-pyrrolidinylidene)-3H-indole, 150 m1. of methanol, and 0.2 g. of platinum oxide catalyst was shaken on a Parr hydrogenation apparatus at 50 lbs. initial pressure of hydrogen. After minutes one equivalent of hydrogen was absorbed. An additional 4 /2 hours of shaking resulted in no additional uptake of hydrogen. The catalyst was removed by filtration and the solvent was removed under reduced pressure on the steam bath. The residual yellow viscous oil was crystallized from Skellysolve B, giving 11.5 g. (91.5% yield) of 5-methyl-3-(l-methyl-Z-pyrrolidinyl)indole free base which sintered at 114 C. and melted between 116- 117.5 C. Recrystallization from ether-Skellysolve B produced colorless prisms, sintering at 115 C. and melting between 116.5-117.5 C.

AnalysisrCalcd. for C H N C, 78.46; H, 8.46; N, 13.08. Found: C, 78.73; H, 8.54; N, 12.34.

EXAM PLE 5 .-1 -BENZYL-3 l-METHYL-Z-PYR- ROLIDINYL) IND OLE A. 1-benyl-3-(1-methyl-2-pyrr0lidinyl) indole free base Phosphorus oxychloride (40.8 g.; 0.26 mole) was add ed with stirring to 60 ml. (0.6 mole) of l-methyl-Z-pyrrolidone cooled in an ice bath at such a rate (25 minutes) that the temperature of the reaction mixture did not exceed C. The yellow paste was stirred an additional 25 minutes while cooling in the ice bath. To this material was added with stirring a solution of 49.7 g. (0.24 mole) of l-benzylindole in 100 ml. (1 mole) of 1-methyl-2-pyrrolidone at such a rate (30 minutes) that the temperature of the reaction mixture did not exceed 15 C. The ice bath was removed and after standing 1% hours the orange solution was heated at 90 C. for 2 hours. The solution was cooled and treated with 750 ml. of water. The mixture was then made basic by the addition of a solution of 60 g. of sodium hydroxide in 300 ml. of water and extracted with three GOO-ml. portions of ether. The combined ether extracts were washed with three 200-ml. portions of water and dried over anhydrous magnesium sulfate. The ether was evaporated on the steam bath, yielding 58.7 g. of light brown oil which darkened on standing.

A mixture of 20 g. or" the brown oil, 400 ml. of absolute ethanol, and 20 g. of sodium borohydride was allowed to stand at 25 C. for 2 days. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 250 ml. of water. The mixture was extracted with two 400-rnl. portions of ether. The combined ether extracts were washed with two -ml. portions of water and dried over anhydrous magnesium sulfate. The ether was evaporated and the residue was distilled at 0.05 mm. The product was 1-benzyl-3-(I-methyl-Z-pyrrolidinyl) indole free base and had a boiling point of 180185 C. at 0.05 mm.

Analysis-Cakd. for C H N C, 82.71; H, 7.64; N, 9.65. Found: C, 82.00; H, 7.16; N, 9.39.

in the manner as shown above, 5-methyl-1-(p-methoxybenzyl)-3-(1-methyl-2-pyrrolidinyl)indole free base, 1- (p-ethoxybenzyl) 2-methyl-3-(1-methyl-2-pyrrolidinyl)- indole free base, 1-(p-propoxybenzy1)-3-(1-methyl-2- pyrrolidinyl)indole free base, and 1-(p-butoxybenzyl)-3- (1-methyl-2-pyrrolidinyl)indole free base were prepared by substituting 5-rnethyl-1-(p-methoxybenzyl)indole, 1- (p ethoxybenzyl)-2-methylindole, 1-(p-propoxybenzyl)- indole, and 1-(p-butoxybenzyl)indole, respectively, for 1- benzylindole.

B. 1 -benzyl-3- (I-methyZ-Z-pyrrolidinyl) indole cyclohexanesulfamate 6.3 g. (0.0216 mole) of 1-benzyl-3-(l-methyl-Z-pyrrolidinyl)indole free base was dissolved in 20 ml. of isopr-opyl alcohol and added to 3.88 g. (0.0216 mole) of cyclohexanesulfamic acid dissolved in 20 ml. of isopropyl alcohol. Anhydrous ether was added until the solution became cloudy. Cooling for 12 hours produced an oily solid. The solvent was decanted whereupon the oil soon solidified. The solid was crystallized from isopropyl alcohol-ether, giving 6.5 g. of 1-benzyl-3-(l-methyl-Z-pyrrolidinyl)indole cyclohexanesulfamate which melted between 127129.5 C.

Analysis.-Calcd. for C26H35N3O3S: C, H, N, 8.95. Found: C, 66.48; H, 7.31; N, 8.91.

EXAMPLE 6.7-METHYL-3-( l-METHYL-Z- PYRROLIDINYLHNDOLE FREE BASE A. 7 -methyl-3 l-m ethy l-2- pyrrolidinyl idcne -3H -ind0le Phosphorus oxychloride (81.6 g.; 0.52 mole) was added with stirring over a period of 50 minutes to 100 ml. (1 mole) of l-methyl-Z-pyrrolidone cooled in an ice bath. The temperature of the reaction mixture did not ex ceed 15 C. The yellow paste was stirred an additional 10 minutes while cooling in the ice bath. To this mixture was then added with stirring a solution of 52.5 g. (0.4 mole) of 7-methylindole in 100 ml. (1 mole) of l-methyl-Z- pyrrolidone during 20 minutes. The temperature did not rise above 15 C. The ice bath was removed and in 7 minutes the temperature rose to 64 C. The ice bath was replaced. When the temperature of the reaction mixture fell to 50 C., the ice bath was again removed. The mixture was then heated at 85 C. for 2 hours, cooled, and treated with 1000 ml. of water. The resulting brown solution was basified by the addition of a solution of g. of sodium hydroxide in 600 ml. of water. The resulting thick paste was diluted with 1000 ml. of water and filtered. The recovered solid was washed well with water and recrystallized from aqueous methanol, giving 79 g. (93% yield) of 7 methyl-3-(1-methyl-2-pyrrolidinylidene)-3H-indole which sintered at 202 C. and melted between 208210 C. (decomp). After four recrystallizations from aqueous 15 methanol the compound sintered at 205 C. and melted between 210212 C. (dec.).

Analysis.Calcd. for C H N C, 79.21; H, 7.60; N, 13.20. Found: C, 79.37; H, 7.54; N, 13.01.

- B. 7-methyl-3-(1-methyI-Z-pyrrolidinyl)indole free base A mixture of 40 g. of 7-methyl-3-(I-methyl-Z-pyrrolidinylidene)-3H-indole, 19 g. of sodium borohydride, and 500 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 300 ml. of water and an oil separated. The mixture was extracted with two 400-ml. portions of ether. The combined ether extracts were washed with two 100-ml. portions of water and dried over anhydrous magnesium sulfate. The ether was evaporated and the residue was crystallized from ether-Skellysolve B, giving a pale yellow solid. The solid was recrystallized from ether-Skellysolve B, giving 29 g. (72% yield) of 7-rnethyl-3-(lmethyl-2-pyrrolidinyl)indole free base which melted between 9397 C. On another recrystallization from ether- Skellysolve B, the compound melted between 9597.5 C.

Analysis.-Calcd. for C H N C, 78.46; H, 8.46; N, 13.08. Found: C, 78.69; H, 8.58; N, 12.89.

EXAMPLE 7.3- l-METHYL-S-ETHYL-2-PYRROL- IDINYL) -INDOLE FREE BASE A. 3-(4-nizr0hexan0yl)indole In the same manner as shown in Example 3, Part A,

3-(4-nitrohexanoyl)indole was prepared by substituting 1- nitropropane for nitroethane. The compound melted between 171-173" C.

B. 3-(5-ethyl-1-pyrr0lin-2-yl)indole In the same manner as shown in Example 3, Part B, 3-(5-ethyl-l-pyrrolin-2-yl)indole was prepared by substituting 3-(4-nitrohexanoyl)indole for 3-(4-nitrovaleryl)indole.

C. 3-(5-ethyl-2-pyrrolidinyl) indole hydrochloride D. 3-(1-methyI-S-ethyI-Z-pyrrolidinyl)indole free base 1) By lithium aluminum hydride reduction.-The 3- (-ethyl-2-pyrrolidinyl)indole hydrochloride of Part C was dissolved in water and basified with aqueous sodium hydroxide solution and extracted with ether. The extracts were Washed with saturated salt solution, dried over anhydrous sodium sulfate, and evaporated to give 3-(5-ethyl-2-pyrrolidinyl)indole free base. A mixture of 3-(5-ethyl-2-pyrrolidinyl)indole free base (0.5 g.; 2.33 millimoles) and ml. of methyl formate was refluxed for hours. The resulting solution was evaporated to dryness to give an oil which showed a strong amide band at 1650 cm." in the infrared spectrum. A solution of this oil in 25 ml. of benzene Was added to a solution of lithium aluminum hydride (0.55 g.) in 50 ml. of ether, and the mixture was refluxed for 18 hours. It was then decomposed in succession with 0.5 ml. of water, 0.5 ml. of 15% aqueous sodium hydroxide solution, and 1.5 ml. of Water. The suspension was stirred for 1 hour and filtered. The filtrate was evaporated to dryness and the resulting solid (0.5 g.) was crystallized from ether-petroleum ether (B.P. 3060 C.) to give 0.42 g. (79% yield) of 3-(l-methyl-5-ethyl-2-pyrrolidinyl)indole free base which melted between 140141 C.

(2) By sodium borohydride reduction.-A solution of 3- (S-ethyl-1-pyrrolin-2-yl)indole (Part B) (2.12 g.; 0.01 mole) in 15 ml. of methanol and 5 ml. of methyl iodide was refluxed for 4 hours under nitrogen. The mixture was allowed to stand for 12 hours and then evaporated to dryness under reduced pressure. Crystallization from methanol-ether alr'orded 1.2 g. of colorless needles of 3-(1- methyl 5 ethyl 2 pyrrolidinylidene) 3H indole hydroiodide, M.P. 157164 C. Recrystallization raised the M.P. to 167169 C. (1.0 g.; 28% yield).

Ultraviolet spectrum (ethanol) showed A sh 246; 251 (12,850); 265 (10,100); 270 (10,550); 332 (19,250).

Analysis.-Calcd. for C H lN C, 50.86; H, 5.40; I, 35.83; N, 7.91. Found: C, 50.80; H, 4.99; I, 35.84; N, 7.79.

Sodium borohydride (2.4 g.) was added during 5 minutes to a solution of 3-(1-rnethyl-5-ethyl-2pyrrolidinylr idene)-3H-indole hydroiodide (2.4 g.; 6.8 millimoles) in ml. of ethanol. The mixture was stirred for 4 hours and then evaporated to dryness. The residue was treated with 100 ml. of water and extracted with ether (three 200ml. portions). The combined ether extracts were washed with saturated salt solution, dried with sodium sulfate, and evaporated to give 2.0 g. of a colorless solid. Crystallization from ether-petroleum ether (B.P. 30-60 C.) gave 1.0 g. (65% yield) of 3-(1-rnethyl-5-ethyl-2- pyrrolidinyl)indole free base, M.P. 139-140 C., raised on recrystallization to 140-141 C.

Ultraviolet spectrum (ethanol) showed Amax, 219.5 (34,750); sh 274 (5,650); 281 (6,100); 289 (5,000).

Analysis.-Calcd. for C H N C, 78.90; H, 8.83; N, 12.27. Found: C, 78.60; H, 8.75; N, 12.45.

Ultraviolet and infrared spectra showed this compound to be identical with that obtained by the lithium aluminum hydride procedure above.

EXAMPLE 8. 1-ETHYL-3-(1 -ETHYL-2-PYR- ROLIDINYL) INDOLE EXAMPLE 9.4,6-DIMETHYL3-( l-PROPYL-Z- PYRROLIDINYL) INDOLE In the same manner as shown in Example 6, 4,6-dimethyl-3-(1-propyl-2-pyrrolidinyl)indole free base was prepared by substituting 4,6dimethylindole and l-propyl- 2-pyrrolidone for 7-methylindole and l-methyl-Z-pyrrolidone to produce 4,6-dimethyl-3-(1-propyl-2-pyrrolidinylidene) -3H-indole and reducing the latter with sodium borohydride.

In the same manner as shown in Example 5B, 4,6-dimethyl-3-(1-propyl-2-pyrrolidinyl)indole sulfate was prepared by substituting 4,6-dimethyl-3-(1-propyl-2-pyrrolidinyl)indole free base and sulfuric acid for 1-benzyl-3- (l-methyl-2-pyrrolidinyl)indole free base and cyclohexanesulfamic acid.

EXAMPLE 10.5 ,7-DIMETI-IYL-3-( l-BUTYL-2-PYR- ROLIDINYL) INDOLE FREE BASE In the same manner as shown in Example 6, 5,7-dimethy1-3-(1-butyl-2-pyrrolidinyl)indole free base was prepared by substituting 5,7-dirnethylindole and 1-butyl-2- pyrrolidone for 7-methylindole and 1-rnethyl-2-pyrrolidone to produce 5 ,7-dimethyl-3-(l-butyl-2-pyrrolidinylidene)-3H-indole and reducing the latter with sodium borohydride.

EXAMPLE 1l.1,7-DIMETHYL-3-(1,3-DIMETHYL- Z-PYRROLIDINYL) INDOLE In the same manner as shown in Example 5A, 1,7-diyl-3'1 3filmethyl-Z-pyrrolidinyl)indole free base 17 was prepared by substituting 1,7-dimethylindole and 1,3- dirnethyl-2-pyrrolidone for l-benzylindole and l-methyl- 2-pyrro1idone.

In the same manner as shown in Example B, 1,7-dimethyl-3-(1,3-dimethyl-2-pyrrolidiny1)indole citrate was prepared by substituting citric acid and 1,7-dimethy1-3- (1,3-dimethyl-2-pyrrolidinyl)indole free base for cyclohexanesuifamic acid and l-benzyl-3-(l-methyl-Z-pyrrolidinyl)indole free base.

EXAMPLE 12.7-ETI-IYL-3-( 1,5-DIMETHYL-2-PYR- ROLIDINYL) IND OLE FREE BASE In the same manner as shown in Example 6, 7-ethy1- 3-(1,5-dimethyl-2-pyrro1idinyl)indole free base was prepared by substituting 7-ethylindole and 1,5-dimethyl-2- pyrrolidone for 7-rnethylindole and l-methyl-Z-pyrrolidone to produce 7-ethyl-3-(1,5-dimethyl-Z-pyrrolidinylidene)-3H-indo1e and reducing the latter with sodium borohydride.

EXAMPLE 13 .1-BENZYL-3-( 1,4-DIETHYL-2- PYRROLIDINYL) INDOLE In the same manner as shown in Example 5A, l-benzyl- 3-( l,4-diethyl-2-pyrrolidiny1)indole free base was prepared by substituting 1,4-diethyl-2-pyrrolidone for l-methyl-Z-pyrrolidone.

In the same manner as shown in Example 5B, l-benzyl- 3-(1,4-diethyl-2-pyrrolidinyl)indole hydrochloride was prepared by substituting 1-benzy1-3-(1,4-diethy1-2-pyrrolidinyl)indole free base and hydrogen chloride for l-benzyl- 3-(l-methyl-Z-pyrrolidinyl)indole free base and cyclohexanesulfamic acid.

EXAMPLE 14.3 1,3 ,5-TRIMETHYL-2- PYRROLIDINYL) INDOLE In the same manner as shown in Example 6, 3-(1,3,5- trimethyl-Z-pyrrolidinyl)indole free base was prepared 'by substituting indole and 1,3,5-trimethy1-2-pyrrolidone for 7-methyl-indole and l-methyl-Z-pyrrolidone to produce 3- (1,3,5 -trimethyl-2-pyrrolidinylidene) 3H indole and reducing the latter with sodium borohydride.

In the same manner as shown in Example 5B, 3-(1,3,5- trimethyi-Z-pyrrolidinyl)indole lactate was prepared by substituting 3-(1,3,5-trimethyl-2-pyrrolidinyl)indole free base and lactic acid for 1-benzyl-3-(1-methyl-2-pyrrolidinyDindole free base and cyclohexanesulfamic acid.

EXAMPLE 15.6-METI-IYL-3-( 1,3,3-TRIMETHYL-2- PYRROLIDINYLHNDOLE FREE BASE In the same manner as shown in Example 6, 6-methyl- 3-(1,3,3-trimethyl-2-pyrrolidinyl)indole free base was prepared by substituting 6-methylindole and 1,3,3-trimethyl- 2-pyrrolidone for 7-methylindole and l-methyl-Z-pyrrolidone to produce 6-methyl-3-(1,3,3-trimethy1-2-pyrrolidinylidene)-3H-indole and reducing the latter with sodium borohydride.

EXAMPLE 16.1,5-DIPROPYL-3 1 -ETHYL-4- PROPYL-Z-PYRROLIDINYL) INDOLE In the same manner as shown in Eample 5A, 1,5-dipropyl-3-(1-ethyl-4-pyropyl 2 pyrrolidinyl)indole free base was prepared by substituting 1-ethyl-4-propyl-2-pyrrolidone and 1,5-dipropylindole for 1-methyl-2-pyrro1idone and l-benzylindole.

In the same manner as shown in Example 5B, 1,5-dipropyl-3-(1-ethyl-4propyl 2 pyrrolidinyl)indole acetate was prepared by substituting 1,5-dipropy1-3-(1-ethyl-4- propyl-Z-pyrrolidinyl)indole free base and acetic acid for 1-benzyl-3-(l-methyl-Z-pyrrolidinyl)indole free base and cyclohexanesulfarnic acid.

EXAMPLE 17.1,6-DIBUTYL-3-( 1,3 ,S-TRIETHYL- 2-PYRROLIDINYL)INDOLE FREE BASE In the same manner as shown in Example 5A, 1,6-dibutyI-3-(1,3,3-triethyl-2-pyrrolidinyl)indole free base was prepared by substituting 1,6-dibutylindole and 1,3,3-tri- 18 ethyl-2-pyrro1idone for l-benzylindole and 1-methyl-2-pyrrolidone.

EXAMPLE 18.4,5-DIPROPYL-3- 1,4-DlETHYL-4- METHYL-Z-PYRROLIDINYL) INDOLE EXAMPLE 19.1-PROPYL-6-ETHYL3-( 1-ETHYL-4- METHYL-Z-PYRROLIDINYL) INDOLE FREE BASE In the same manner as shown in Example 5A, l-propyl- 6-ethyl-3-(1-ethyl-4-methyl-2-pyrrolidiny1)indole free base was prepared by substituting 1-propyl-6-ethylindole and 1-ethyl-4-methyl-2-pyrrolidone for l-benzylindole and lmethyl-Z-pyrrolidone.

EXAMPLE 20.-1BUTYL-4-METHYL-7-ISOPROPYL- 3-( 1 BUTYL-3,3-DIETHYL-2-PYRROLIDINYL)IN- DOLE FREE BASE In the same manner as shown in Example 5A, l-butyl- 4-metl'1yl-7-isopropyl-3-(1-butyl-3,3-diethyl 2 pyrrolidinyl)indole free base was prepared by substituting 1- butyl-4-rnethyl-7-isopropylindole and 1-butyl-3,3-diethyl- 2-pyrrolidone for l-benzylindole and 1-methyl-2-pyrrolidone.

EXAMPLE 21.1 BENZYL-5METHYL-3-( l-METH- YL-S-BUTYL 2 PYRROLIDINYLHNDOLE FREE BASE In the same manner as shown in Example 5A, l-benzyl- S-methyl 3 (1-methyl-5-butyl-Z-pyrrolidinyl)indole free base was prepared by substituting l-benzyl-S-methylindole and 1-methyl-S-butyl-Z-pyrrolidone for l-benzylindole and l-methyl-Z-pyrrolidone.

EXAMPLE 22.3- 1-ETHYL-5 ,5 -DIMETHY L-Z-PYR- ROLIDINYL)INDOLE FREE BASE A. 3-(4-methyl-4-nitr0valeryl) indole In the same manner as shown in Example 3, Part A, 3-(4-rnethyl-4-nitrovaleryl)indole was prepared by substituting Z-nitropropane for nitroethane. The compound melted between 203204 C.

B. 3-(5,5 -dimethyl-1 -pyrr0lin-2-yl indole In the same manner as shown in Example 3, Part B, 3- (5,5-dimethyl-1-pyrrolin-2-yl)indole was prepared by bydrogenating 3-(4-rnethyl-4-nitrovaleryl)indole instead of 3-(4-nitrovaleryl)indole. The compound melted between 197-198 C.

Ultraviolet spectrum (ethanol) showed k 219 (26,700); 255 (11,650); 271 (10,150); 289 (11,350); sh 300 (8,800); sh 330 (2,400).

Analysis.Calcd. for C H N C 79.21; H, 7.60; N,

13.20. Found: C, 7910,11, 7.19; N, 13.23.

C. 3-(5,5-dimethyl-Z-pyrrolidinyl)indole free base In the same manner as shown in Example 3, Part C, 3-(5,S-dimethy1-2-pyrrolidiny1)indole hydrochloride was prepared by substituting 3-(5,5-dimethyl-1-pyrrolin-2-yl) indole for 3-(5-methy1-1-pyrrolin-2-yl)indole. The compound melted between 229230 C. (dec.). The hydrochloride was dissolved in water and basified with 15% aqueous sodium hydroxide solution and extracted with ether. The combined extracts Were washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated, to give 3-(5,5-dimethyl-Z-pyrrolidinyl)indole free base melting between 104.5106 C.

D. 3-(1-acetyl-5,5-dimethyl-Z-pyrrolidinyl)indole 6 g. (0.0028 mole) of 3-(5,S-dimethyl-Z-pyrrolidinyl) indole free base was dissolved in 60 ml. of acetic anhydride and the solution was allowed to stand for 12 hours at 25 C. The resulting suspension was filtered and the solid was washed with ether to obtain 4.4 g. of 3-(1-acetyl- 5,5-dimethyl-2-pyrrolidinyl)indole which melted at 204 206 C.

Analysis.-Calcd. for C H N O: C, 74.96; H, 7.86; N, 10.93. Found: C, 74.86; H, 8.20; N, 10.86.

E. 3-(1-ethyl-5,5-dimethyl-Z-pyrrolidinyl)indole free base A solution of 3-(1-acetyl-5,5-dimethyl-Z-pyrrolidinyl) indole (0.6 g.; 2.34 millimoles) in 100 ml. of benzene was added to a solution of lithium aluminum hydride (0.6 g.) in 100 ml. of benzene. The mixture was refluxed for 12 hr. and was then allowed to stand for 24 hr. The mixture was decomposed by the successive addition of 1 ml. of water, 1 ml. of 15% sodium hydroxide solution, and 3 ml. of water. The mixture was filtered and the filtrate was evaporated to dryness to give 0.5 g. of an oil. Crystallization from petroleum ether (B.P. 3060 C.) afforded 0.45 g. (80% yield) of 3-(1-ethyl-5,5-dimethyl-2-pyrrolidinyl) indole free base which melted between 8285' C.

Analysis.Calcd. for C H N C, 79.29; H, 9.15; N, 11.56. Found: C, 79.14; H, 9.33; N, 11.29.

EXAMPLE 23.-3- 1 ,5,5-TRIMETHYL-2-PYR- ROLIDINYL)INDOLE FREE BASE A solution of 24.84 g. (0.116 mole) of 3-(5,5-dimethyl- 2-pyrrolidinyl)indole free base (Example 22C) in 350 m1. of methanol and 116 ml. of methyl iodide was refluxed under nitrogen for 48 hrs. It was evaporated to dryness under reduced pressure and the residue was triturated with methanol. The resulting solid was dissolved in 500 ml. of water. The solution was cooled, basified'with sodium hydroxide, and extracted with methylene chloride. The extract was washed with saturated salt solution, dried over sodium sulfate and evaporated, to give 18.8 g. of an oily solid. The solid was chromatographed on 300 g. of silica. Elution with 3150 ml. of ethyl acetate afforded 3-(1,5,S-trimethyl-2+pyrrolidinyl)indole free base, which on recrystallization from ether-petroleum ether (B.P. 30- 60 C.) weighed 6.9 g. (26% yield) and melted between 138-140 C.

Analysis.Calcd. for C H N C, 78.90; H, 8.83; N, 12.27. Found: C, 78.48; H, 8.74; N, 12.26.

EXAMPLE 24.l -METHYL-3-( l-METHYL-Z-PYR- ROLIDINYLHNDOLE FREE BASE A. 3-(1-methyl-2-pyrr0lidinylidene) -3H-indole In the same manner as shown in Example 3A, 3-(4- nitrobutyryl)indole was prepared by substituting nitromethane for nitroethane. The compound melted between The 3-(4-nitrobutyryl)indole was reduced and concomitantly cyclized utilizing Raney nickel catalyst in the manner described in Example 3B to produce 3-(1-pyrrolin- 2-yl)indole which melted between 182.5183.5 C.

Methyl iodide ml.) was added to a solution of 3- (l-pyrrolin-2-yl)ind0le (9.2 g.; 0.05. mole) in 75ml. of methanol and the solution was refluxed for 1.5 hr. The

resulting suspension was cooled in ice and filtered to give 11.3 g. yield) of 3-(l-methyl-2-pyrrolidinylidene)- 3H-indole hydroiodide melting between 270-283 C. Two recrystallizations from methanol aiiorded long needles, darkening at 280 C. and melting between 293-296 C. (dec.).

A suspension of 3-(1-methyl-2-pyrro1idinylidene)-3H- indole hydroiodide (1.6 g.; 0.005 mole) in 10 ml. of water, 25 ml. of benzene, 30 ml. of 1 N sodium hydroxide, 25 ml. of methylene chloride, and 10 ml. of methanol was shaken until two clear layers resulted. The aqueous layer was extracted twice with methylene chloride and the combined extracts were washed with saturated salt solution, dried over anhydrous sodium sulfate and evaporated, to give 0.9 g. (91% yield) of 3-(l-methyl-2-pyrrolidinylidene)-3H-indole free base.

Alzalysis.Calcd. for C H N C, 78.75; H, 7.12; N, 14.13. Found: C, 78.44; H, 6.74; N, 13.88.

B. 3-(1-methyI-Z-pyrrolidinylizlene) -3H-ind0le methiodide A solution of 3-(1-methyl-2-pyrrolidinylidene)-3H- indole free base (0.5 g.) in 1 0 ml. of methanol and 5 ml". of methyl iodide was refluxed under nitrogen for 24 hrs. The solution was evaporated to dryness to produce 3-(1- methyl-Z-pyrrolidinylidene)-3H-indole methiodide which melted between 248-250 C. After recrystallization from methanol, the compound melted between 249-250 C.

Analysis.-Calcd. for C14H1'1N2: C, 49.42; H, 5.04; I, 37.30; N, 8.24. Found: C, 49.25; H, 4.63; I, 37.05; N, 8.39.

C. l-metlzyl-3-(1-methyl-Z-pyrrolidinyl)indole free base The 3 (1 methyl 2 pyrrolidinylidene) 3H indole methiodide (Part B) was dissolved in 75 ml. of hot ethanol, the solution was cooled to about 60 C., and treated with 1 g. of sodium borohydride. The resulting solution was stirred at 25 C. for 21 hrs. and evaporated under reduced pressure. Water was then added and the mixture was extracted twice with ether. The combined extracts were washed with water, saturated salt solution, dried over anhydrous sodium sulfate and evaporated, to give 0.536 g. of an oily solid. The solid was dissolved in 10 ml. of acetone and chromatographed on 10 g. of silica (50-200 mesh). Elution with four'20-ml. portions of I the 1-methyl-3(1-methyl-2-pyrrolidinyl)indole free base prepared in Example 2A.

EXAMPLE 25 .3-( l-METHYL-2-PIPERIDYL) INDOLE FREE BASE Phosphorus oxychloride (30.7 g; 0.2 mole) was added to 25 g. (0.22 mole) of -l-methyl-2-piperidone with stir ringat such a rate that the temperature of the reaction mixture did not exceed 15 C. while cooled in an ice bath. The resulting thick yellow paste was stirred an additional 55 minutes while cooled in the ice bath. To this material was added during 1 hour with stirring a solution of Zli g. (0.18 mole) of indole in 25 g. (0.22 mole) of 1-methyl- 2-piperidone. The temperature did not rise above 10 C. The ice bath was removed and after 15 minutes the temperature had risen to 38 C. The mixture was heated for 2 hours at C. After standing overnight at about 25 C. the brown viscous liquid set to a glassy solid. This material was treated with 800 ml. of water and the resulting solution was filtered to remove a small amount of in soluble material. The filtrate was basified by the addition of a solution of 44 g. of sodium hydroxide in 220 ml. of water. The resulting paste was filtered and the filter cake was washed with 300 ml. of water. The cake was crystallized from aqueous ethanol, giving 33 g. of yellow solid which sintered at C. and melted between 109- 112 C.

Sodium (15 g.; 0.65 mole) was added in portions during 1.5 hours to a refluxing solution of 12.8 g. of the above yellow solid in 250 ml; of n-butanol, and refluxing was continued for 1 hour thereafter. The solution was cooled and 110 ml. of water was added, followed'by 500 ml. of ether. The organic layer was separated, washed with three 100-ml. portions of water, and concentrated to dryness on i a steam bath by distillation, first at atmospheric pressure and then at reduced pressure. The red oil thus obtained acid. The combined acid extracts were basified with aqueous sodium hydroxide solution, and the resulting alkaline mixture was extracted with three 250-ml. portions of ether. The combined ether extracts were washed with two ZOO-ml. portions of water and dried over anhydrous magnesium sulfate. The dried solution was concentrated to 200 ml. on a steam bath and Skellysolve B was added until the solution became cloudy. A sticky solid was obtained by cooling the cloudy solution in an acetone-solid carbon dioxide bath. The sticky character of the solid was not changed by recrystallization from ether- Skellysolve B with cooling in a cold bath as above. Crystalline material was obtained by recrystallizing the sticky solid from aqueous acetone. The crystalline material was recrystallized from ether-Skellysolve B to obtain 3-(1- methyl-Z-piperidyl)indole free base as pale yellow crystals melting between 155-156 C. An additional quantity of 3-(1-methyl-2-piperidyl)indole free base was obtained from the mother liquors.

EXAMPLE 26.4-CHLORO-3 l-VIETHYL-Z- PYRROLIDINYL) INDOLE FREE BASE A. 4 -chlr0-3 (1 -m ethyl-Z-pyrrolidinylid ene) -3H-irzd0l e Phosphorus oxychloride (40.8 g.; 0.26 mole) was added with stirring to 50 ml. (0.5 mole) of 1-methyl-2-pyrrolidone cooled in an ice bath at such a rate (25 minutes) that the temperature of the reaction mixture did not exceed 15 C. The yellow paste was stirred an additional minutes while cooled in the ice bath. To this material was added with stirring a solution of 20 g. (0.132 mole) of 4-chloroindole in 75 ml. (0.75 mole) of l-methyl-Z- pyrrolidone during minutes. The orange solution was heated at 85 C. for 2 hours. The green solution was treated with 1 liter of water. An oil separated. The mixture was extracted with two 600-ml. portions of ether. The aqueous layer was basified by the addition of a solution of 70 g. of sodium hydroxide in 300 m1. of water A yellow solid begin separating after several hours. The mixture was allowed to stand for 12 hours. The solid was collected by filtration and washed with water, giving 15.1 g. (49% yield) of 4-chloro-3-(l-methyl-Z-pyrrolidinylidene)-3Hindole. A portion was recrystallized three times from aqueous methanol, afiording pale green plates, sintering at 165 C. and melting between 169172 C.

Analysis.-Calcd. for C H ClN C, 67.10; H, 5.63; Cl, 15.23; N, 12.04. Found: C, 67.17; H, 5.78; C1, 1533; N, 11.70.

B. 4-chl0r0-3-(1-meZhyl-2-pyrrolidinyl)indole free base A mixture of 13.15 g. of 4-chloro-3-(l-methyl-Z-pyrrolidinylidene)-3H-indole, 8 g. of sodium borohydride, and 300 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. An additional 7 g. of sodium borohydride and 200 ml. of absolute ethanol were then added and the mixmre was allowed to stand an additional 3 days at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 400 ml. of water. A solid separated. The mixture was extracted with two 400-ml. portions of ether. The combined ether extracts were washed with three ZOO-ml. portions of water and dried over anhydrous magnesium sulfate. The ether solution was concentrated, Skellysolve B was added, and evaporation was continued until crystals separated. Cooling produced 9.15 g. of pale yellow prisms, M.P. 148 152.5 C. Recrystallization from acetone-Skellysolve B gave 7.8 g. (59% yield) of 4-chloro-3-(1-methyl-2-pyrrolidinyl)indole free base as pale yellow prisms, MP. 157- 158.5 C. Recrystallization from acetone-Skellysolve B gave colorless prisms, IVLP. 157-158.5 C.

Ultraviolet spectrum (ethanol) showed 1 223 (38,050); sh 276 (6,100); 282 (6,700); sh 290 (6,000).

Analysis.-Calcd. for C H ClN C, 66.53; H, 6.44; Cl, 15.11; N, 11.94. Found: C, 66.58; H, 6.44; Cl, 15.10; N,11.53.

22 EXAMPLE 27.5-BROMO-3-(1-METHYL-2- PYRROLIDINYL) INDOLE FREE BASE A. 5-br0m0-3- (1-methyI-Z-pyrrolidinylidene) -3H-ind0le Phosphorus oxychloride (40.8 g.; 0.26 mole) was added with stirring to ml. (0.75 mole) of I-methyI-Z-pyrrolidone cooled in an ice bath at such a rate (25 minutes) that the temperature of the reaction mixture did not exceed 15 C. The yellow paste was stirred an additional 10 minutes while cooled in the ice bath. To this material was added with stirring a solution of 47.1 g. (0.24 mole) of 5-br0moindole in 75 ml. of l-methyl-Z-pyrolidone during 12 minutes. The ice bath was removed. The red solution was allowed to stand for 40 minutes and was then heated at C. for 2 hours. The brown solution was treated with 1 liter of water, giving an orange solution. The solution was basified by the addition of a solution of 60 g. of sodium hydroxide in 300 ml. of water. The solid which separated was collected by filtration and washed with water. Recrystallization from aqueous methanol gave 55 g. (82% yield) of 5-bromo-3-(1-methyl-2- pyrrolidinylidene)-3H-indole as buff crystals, sintering at 200 C. and melting between 205208 C. (dec.). A portion was recrystallized twice from aqueous methanol giving bufi plates, sintering at 202 C. and melting between 207210 C. (dec.).

Analysis.Calcd. for C13H13BI'N2: C, 56.32; H, 4.73; Br, 28.83; N, 10.11. Found: C, 56.39; H, 4.59; Br, 28.85; N, 9.61.

B. 5-br0mo-3-(I-methyl-Z-pyrroliclinyl)indole free base A mixture of 35 g. of 5-'bromo-3-(1-methyl-2-pyrrolidinylidene)-3H-indole, 18 g. of sodium borohydride, and 600 ml. of absolute ethanol was allowed to stand for 16 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 400 ml. of water. A solid separated. The mixture was extracted with two 400-ml. portions of ether. The combined ether extracts were Washed with three 200-ml. portions of water, treated with charcoal, and dried over anhydrous magnesium sulfate. The ether solution was concentrated, Skellysolve B was added, and evaporation was continued until crystals began separating. Cooling produced 31.3 g. of ivory prisms, Ml. 127132 C. Recrystallization from acetone-Skellysolve B (charcoal) gave 25.5 g. (72% yield) of 5-bromo-3-(l-methyl-Z-pyrrolidinyl)indole free base as ivory prisms, MP. 136139.5 C. Recrystallization from acetone-Skellysolve B arTorded ivory prisms, MP. 139-141 C.

Ultraviolet spectrum (ethanol) showed A 226 (36,150); sh 284 (5,250); 289 (5,650); sh 298 (4,400).

Analysis.Calcd. for C H BrN C, 55.92; H, 5.42; Br, 28.62; N, 10.04. Found: C, 56.12; H, 5.25; Br, 28.52; N 9 62 EXAMPLE 2S.--3 (1 BUTYL Z-PYRROLTDINYL) P'JDOLE CYCLOHEXANESULFAMATE ETHA- NOL SOLVATE A. 3-(] -butyl-2-pyrr0lidinylidene)-3H-ind0le Phosphorus oxychloride (40.8 g.; 0.26 mole) was added with stirring to 62 g. (0.44 mole) or" l-butyl-2-pyrrolidone (Adams et al., J. Amer. Chem. Soc. 64, 2588, 1942) cooled in an ice bath at such a rate (25 minutes) that the temperature of the reaction mixture did not exceed 15 C. The yellow solution was stirred an additional 10 minutes while cooled in the ice bath. To this material was added with stirring a solution of 28 g. (0.24 mole) of indole in 50 g. (0.35 mole) of l-butyl-Z-pyrrolidone during 15 minutes. The temperature did not rise above 10 C. The ice bath was removed and in 18 minutes the temperature had risen to 75 C. and then began falling. The orange solution was heated at 85 C. for 2 hours. The red solution was treated with 1000 ml. of water, giving a clear orange solution. The solution was extracted with two 500-ml. portions of ether. The aqueous layer was basified by the crystallized from ethanol-ether,

addition of a solution of 60 g. of sodium hydroxide in 300 ml. of water. A yellow oil separated. The mixture was extracted with two 700-ml. portions of ether. The combined ether extracts were washed with two BOO-ml. portions of Water and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and was washed with warm benzene to dissolve some product which had precipitated. The solution was concentrated, Skellysolve B was added, and the solution was concentrated further. Cooling produced 54.5 g. of yellow needles. Recrystallization from acetone-Skellysolve B gave 51 g. of bufi crys tals. Recrystallization from acetone-Skellysolve B (charcoal) gave 43.5 g. (75% yield) of buff needles which sintered and then melted between 129-132 C. A portion was recrystallized twice from acetone-Skellysolve B, atfording 3-(1-butyl-2-pyrrolidinylidene)-3H-indole as pale green needles which sintered at 127 C. and melted between 131134 C.

Analysis.Calcd. for C H N C, 79.95; H, 8.39; N, 11.66. Found: C, 79.95; H, 8.22; N, 11.48.

B. 3-(1-butyl-2-pyrr0lidinyl)indole cyclohexane sulfamate ethanol solvate V A mixture of 47 g. of 3-(1-butyl-2-pyrrolidinylidene)- 3H-indole, 21 g. of sodium borohydride, and 500 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 400 ml. of water. An oil separated. The mixture was extracted with two 400-ml. portions of ether. The combined ether extracts were washed with three 200-ml. portions of water and dried over anhydrous magnesium sulfate. The ether was evaporated, yielding 44.5 g. of 3-(1-butyl-2- pyrrolidiny1)indole free base as a yellow oil. A 44 g. (0.181 mole) portion of 3-(1-butyl-2-pyrrolidinyl)indole free base and 32.5 g. (0.181 mole) of cyclohexanesulfamic acid were dissolved in 100 ml. of warm absolute ethanol. Anhydrous ether was added until the cloud point was reached. Cooling produced a solid. The solid was giving 74 g. (87% yield) of colorless needles, sintering at 115 C. and melting between 11912l C. A portion was recrystallized once from ethanol-ether and twice from ethanol, affording colorless needles of 3-(l butyl 2'pyrrolidinyl)indole cyclohexanesulfamate ethanol solvate, sintering at 114 C. and melting between 116-118 C.

Ultraviolet spectrum (ethanol) showed A 214 (41,500); sh 275 (6,150); sh 280 (6,150); 287 (5,600).

A nalysis.-C alcd. for CZZH35P'I3O3S C, 61.63; H, 8.83; N, 8.98; S, 6.86. Found: C, 61.69; H, 8.41; N, 9.36; S, 7.17.

EXAMPLE 29.3-( 1-ETHYL-2-PYRROLIDINYL) INDOLE HYDROCHLORIDE A. 3-(1-ethyZ-Z-pyrrolidinyliaene)-3 H-indle Phosphorus oxychloride (40.8 g.; 0.26 mole) was .added with stirring to 49 g. (0.43 mole) of 1-ethyl-2-pyrindole in 49 g. (0.43 mole) of 1-ethyl2-pyrrolidone during minutes. The temperature did not rise above 10 C. The ice bath was substituted by a warm Water bath. In about 5 minutes the temperature began rising rapidly. When the temperature of the reaction mixture reached 85. C. the water bath was replaced by an ice bath. The mixture formed a thick paste. The paste was heated at 80 C. for 2 hours and was then dissolved in 1 liter of water, giving a clear orange solution. The solution was basified by the addition of a solution of 60 g. of sodium hydroxide in 300 ml. of water. Thesolid which separated was collected by filtration and washed with water. Crys- 24 tallization from aqueous methanol gave 48.5 g. yield) of yellow needles, M.P. 157-159 C. (dec.) with sintering at 154 C. A portion was recrystallized twice from acetone-Skellysolve B, affording 3-(1-ethyl-2-pyrrolidinylidene)-3H-indole as colorless needles sintering at a 155 C. and melting between -162 C. (dec.).

Analysis.-Calcd. for C H N C, 79.21; H, 7.60; N, V

13.20. Found: C, 78.91; H, 7.35; N, 12.90.

B. 3-(1-ethyl-2-pyrr0lidinyl)indole hydrochloride A mixture of 45.5 g. of 3-(l-ethyl-2-pyrrolidinylidene)- 3H-indole, 24 g. of sodium borohydride, and 500 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 500 ml. of water. An oil separated. The mixture was extracted with two 400-ml. portions of ether. The combined ether extracts were washed with three 200-ml. portions of water, treated with charcoal, and dried over anhydrous magnesium sulfate. The ether was almost completely evaporated, 800 ml. of Skellysolve B was added, and the volume was reduced to 300 ml. The solution was slurried with a filter aid and filtered. Cooling in the freezer produced a solid which was recrystallized from ether-Skellysolve B, giving 40 g. of pale yellow prisms, M.P. 6070 C. (sint. 55 C.). One recrystallization from ether-Skellysolve B, giving 40 g. of pale yellow prisms, tone-Skellysolve B afforded ivory prisms, M.P. 6673 C. (sint. 57 C.). A 15.8 g. portion of material with M.P. 6373 C. (sint. 55 C.) was dissolved in 200 ml. of anhydrous ether and the solution was treated with ethereal hydrogen chloride. The crude hydrochloride was collected by filtration and crystallized from ethanol-ether, giving 16.7 g. of colorless plates of 3-(l-ethyl-2-pyrrolidinyl) indole hydrochloride, M.P. 198-200 C. (sint. 196 C.). Recrystallization from ethanol-ether afforded colorless plates, M.P. 200-202 C. (sint. 198 C.).

Ultraviolet spectrum (ethanol) showed A 214 Analysis.-Calcd. for C H ClN C, 67.04; H, 7.64; Cl, 14.14; N, 11.18. Found: C, 66.77; H, 7.20; Cl, 13.97; N, 11.07.-

EXAMPLE 30.--3-( 1,4-DIMETHYL-2-BYRROLI- DlNYL) INDOLE HYDROCHLORIDE A. 1,4-dimethyl-Z-pyrrolidone A mixture of 23.5 'g. of fi-methylbutyrolactone' Phosphorus oxychloride (20.4 g.; 0.13 mole) was added with stirring during 25 minutes to 8 g. (0.0706 mole) of 1,4-dimethyl-Z-pyrrolidone cooled in an ice bath. The red solution was stirred an additional 10 minutes while cooled in the ice bath. To this material cooled in an ice bath was added with stirring a solution of 8.3 g. (0.0706 mole) of indole in 8 g. (0.0706 mole) of 1,4-dirnethyl-2-pyrrolidone during 15 minutes. The red solution was heated at 90 C. for 2 hours and then was treated with 300 ml. of water. The solution was basified by the addition of a solution of 30 g. of sodium hydroxide in 150 ml. of water. The resulting thick paste was diluted with 400 ml. of water, filtered, and the pink solid was washed with water. Crystallization from aqueous methanol (charcoal) gave 6.2 g.f

dimethyl 2 pyrrolidinylidene) 3H indole was 7.9 g. V

C. 3-(I,4-zlimethyl-Z-pyrrolidinyl) indole hydrochloride A mixture of 6.9 g. of 3-(1,4-dimethyl-Z-pyrrolidinylidene)-3Hindole, 8 g. of sodium borohydride, and 400 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 300 ml. of water. The mixture was extracted with two 400-m1. portions of ether. The combined ether extracts were washed with two 200-ml. portions of water and dried over anhydrous magnesium sulfate. The ether solution containing 3-( l,4-dimethyl-2-pyrrolidinyl)indole free base was treated with ethereal hydrogen chloride. The sticky solid which separated was crystallized from methanolether, giving 5.3 g. of brown crystals. Recrystallization from methanol-ether (charcoal) gave 4.2 g. (51% yield) of tan prisms, M.P. 197-200 C. Recrystallization from methanol-ether afforded ivory prisms of 3-(l,4-dimet'hyl- 2-pyrrolidinyl)indole hydrochloride, M.P. 197-200 C.

Ultraviolet spectrum (ethanol) showed k 214 (44,100); 270 (6,700); sh 276 (6,700); 279 (6,700); 287 (6,000).

Annlysis.-Calcd. for C H CIN C, 67.04; H, 7.64; Cl, 14.14; N, 11.18. Found: C, 66.67; H, 7.67; Cl, 14.21; N, 11.08.

EXAMPLE 3 1.3-( 1,3 -DlMETHYL-2-PYRROLI- DINYL) INDOLE HYDROCHLORTDE A. 3-(Q-methyl-3-(iimethylaminopropionyl)indole methiodide methanol solvate To a solution of 62.8 g. (0.272 mole) of 3-(2-methyl- 3-dimethylaminopropionyl)indole (U.S. Patent 3,037,- 991) in 300 ml. of methanol cooled in an ice bath was added 426 g. (0.3 mole) of methyl iodide. After 30 minutes the ice bath was removed and crystals soon began separating. The reaction mixture was allowed to stand for 12 hours at 25 C. and was then cooled to give 100 g. (91% yield) of nearly colorless prisms. A portion was recrystallized twice from methanol and once from ethanol, giving colorless prisms of 3-(2-methyl-3-dimethylaminopropionyl) indole methiodide methanol solvate, M.P. 174l77 C. (dec.).

Armlysi.r.Calcd. for C H IN O-CH OHZ C, 47.53; H, 6.23; I, 31.39; N, 6.93. Found: C, 47.92; H, 6.17; I, 31.30; N, 7.02.

B. 3-(2-methyl-3-cyan0propi0nyl)indole A m xture of 8.9 g. (0.022 mole) of 3-(2-methyl-3-dimethylaminopropionyl)indole methiodide methanol solvate, 5 g. (0.102 mole) of sodium cyanide, and 50 ml. of dimethylforrnamide was heated on the steam bath for 272 hours. The mixture was poured into 800 ml. of water and cooled in an ice bath. The solid which separated was collected by filtration and washed with water. The solid was crystallized from acetone-Skellysolve B (charcoal), giving 3.05 g. (65% yield) of colorless crystals, M.P. 166-169 C. A portion was recrystallized twice from acetone-Skellysolve B, affording colorless prisms of 3-(2- methyl-3-cyanopropionyl)indole, M.P. 168.5l70 C.

Annlysis.Calcd. for C H N O: C, 73.56; H, 5.70; N, 13.20. Found: C, 73.05, 73.69; H, 5.80, 6.27; N, 12.96.

C. 3-(3-methyl-1-pyrro lirz-2-yl) indole A mixture of 2.5 g. of 3-(2-methyl-3-cyanopropionyl) indole, 150 ml. of ethanol, and a teaspoon of Raney nickel catalyst was shaken on a Parr apparatus at 49.5 lb. initial hydrogen pressure. After 27 hours the hydrogen uptake ceased. The catalyst was removed by filtration and the solvent was removed under reduced pressure. The oily residue was crystallized from acetone-Skellysolve B, giving 1.8 g. (77% yield) of brown crystals, M.P. 137.5

141 C. (sint. C.). Two recrystallizations from acetone-Skellysolve B aitorded brown prisms of 3-(3-methyl- 1-pyrrolin-2-yl)indole, M.P. 144146 C. (sint. 141 C.).

Ultraviolet spectrum (ethanol) showed Amax 218.5 (24,700); sh 250 (10,550); 256 (11,650); sh 273 (9,600); sh 280 (10,450); 291 (11,650); sh 330 (1,500).

Analys.'s.Calcd. for C13H14N2: C, 78.75; H, 7.12; N, 14.13. Found: C, 78.67; H, 7.23; N, 13.97.

D. 3-(1,3-'limethyI-Z-pyrrolidinyl)indole hydrochloride 1) By lithium aluminum hydride reclucZi0n.A mixture of 9.1 g. of 3-(3-methyl-l-pyrrolin-2-yl)indole, 0.4 g. of platinum oxide catalyst, and ml. of methanol was shaken on a Parr apparatus at 49.5 lb. initial hydrogen pressure. A-ter 21 hours one equivalent of hydrogen was absorbed. The catalyst was removed by filtration and the solvent was removed under reduced pressure on the steam bath. The residual brown oil, 3-(3-methyl-2- pyrrolidinyl)indole free base, and 200 ml. of methyl formate was heated under reflux for 3 days. The excess methyl formate was removed under reduced pressure on the steam bath. The residue was shaken with 800 ml. of ether. The ether solution was extracted with two 150-m1. portions of 2 N hydrochloric acid, washed with three 200-ml. portions of water, and dried over anhydrous magnesium sulfate. The ether was evaporated, giving 4.7 g. of brown oil. The oil was dissolved in a mixture of 50 ml. of dry benzene and 50 ml. of dry ether. The solution was added during 30 minutes to a stirred suspension of 7 g. of lithium aluminum hydride in 250 ml. of dry ether. The mixture was heated under reflux for 22 hours, cooled in an ice bath, and decomposed by the addition of 50 ml. of water, followed by 50 ml. of 15% aqueous sodium hydroxide solution. The organic layer was decanted from the thick inorganic paste. The paste was stirred with two 250ml. portions of ether followed by decantation. The combined ether extracts were washed with two 200-ml. portions of water and dried over anhydrous magnesium sulfate. The ether was evaporated. The oily residue, 3- (1,3-dimethyl-2pyrrolidinyl)indole free base, was dissolved in 150 ml. of ether and treated with ethereal hydrogen chloride. The solid was filtered and crystallized twice from methanol-isopropanol-ether, giving 2.7 g. (23% yield) of pale pink needles, M.P. 208-21 1 C. Two rccrystallizations from methanol-isopropanol-ether afforded ivory needles of 3(l,3-dimethyl-2pyrrolidinyl) indole hydrochloride, M.P. 2l12l4 C.

Ultraviolet spectrum (ethanol) showed )t 214 (43,650); 270 (6,650); sh 277 (6,650); 278.5 (6,700); 286 (5,900).

Analysis.Calcd. for C H CIN C, 67.04; H, 764; C1, 14.14; N, 11.18. Found: C, 67.03; H, 7.49; CI, 14.05; N, 10.99.

(2) By sodium borohyzlride reduction-A mixture of 2.1 g. of 3-(3-methyl-l-pyrrolin-2-yl)indole (Part C), 5 ml. of methyl iodide, and 75 ml. of methanol was heated under reflux for 2% hours. The methanol and excess methyl iodide Were removed under reduced pressure on the steam bath, yielding 3-(l,3-dimethyl-Z-pyrrolidinylidene)-3-H-indole hydroiodide as a brown oil. The oil was dissolved in 100 ml. of absolute ethanol and 5 g. of sodium borohydride was added. The mixture was allowed to stand at 25 C. for 2% days. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 100 m1. of water. The mixture was extracted with two 150-m1. portions of ether. The combined ether extracts were washed with three 100-ml. portions of water and dried over anhydrous magnesium sulfate. The solution was concentrated, Skellysolve B was added, and the solution was again concentrated. Cooling caused a small amount of solid to separate which was removed by filtration through charcoal. The filtrate was treated with ethereal hydrogen chloride. The solid was filtered and crystallized from methanol-ether. Two recrystallizations from methanol-isopropanol-ether gave 0.52 g. (19.5% yield) of 3-( l,3-dimethyl2-pyrro1idinyl)indole hydrochlo- Z7 ride as pale pink needles, M.P. 209213 C. A mixed melting point of this material with that obtained by the above lithium aluminum hydride procedure was not (1..- pressed.

EXAMPLE 3 2.--METHOXY-3 1 -METHYL-2- PYRROLIDINYLHNDOLE FREE BASE A. 5-meth0iy-3-(1-methyI-Z-pyrrolinylidene)- 3H-ind0le Phosphorus oxychloride (40.8 g.; 0.26 mole) was slowly added at C. (ice bath cooling) to 40 ml. of 1- methyl-Z-pyrrolidone. After the addition was complete the mixture was stirred for minutes and a solution of 28.0 g. (0.19 mole) of S-methoxyindole and 40 ml. of 1-methyl-2-pyrrolidone was slowly added. The ice bath was removed and the mixture was allowed to warm to 35 C. When the temperature began to rise the flask was quickly immersed in an ice bath. The temperature was i then held at 70 C. When the temperature began to drop the solution was heated for 1 hour at 65 C., then cooled and ice was added. Enough water was then added to dissolve the mixture. The mixture was filtered and the filtrate was treated with sodium hydroxide, cooled, and filtered. The resulting solid was washed with water and recrystallized from about 50% ethanol to yield 37.8 g. (88% yield) of S-methoxy 3-(1-methyl-2-pyrrolidinylidene) 3H-indole; M.P. 202204 C.

Analysis.-Calcd. for C I-1 N 02 C, 73.65; H, 7.06; N, 12.27. Found: C, 73.66; H, 7.40; N, 12.46.

In the same manner as shown above, 5,6 dimethoxy- 3-(1 methyl 2 pyrrolidinylidene) 3H-indole, 5- ethoxy 2 methyl 3 (1 methyl-2-pyrrolidinylidene) 3H-indole, 5 propoxy-3-(1-methyl-2-pyrrolidinylidene)- 3H-indole, and 6 butoxy 3 (l-rnethyl 2-pyrrolidinylidene) 3l-l-indole were prepared by substituting 5,6-dimethoxyindole, S-ethoxy 2 methylindole, 5-propoxyindole, and 6-butoxyindole, respectively, for S-methoxyindole.

B. 5-meth0xy-3-(1-methyl-Z-pyrrolidinyl)indole free base 4.0 g. (0.017 mole) of S-methoxy 3 (1 methyl- 2 pyrrolidinylidene)-3H-indole was gradually added in the solid state to a mixture of 2.5 g. of lithium aluminum hydride in 100 ml. of tetrahydrofuran. The mixture was refluxed for 4 hours, cooled, and decomposed with wet ether. Water was slowly added followed by concentrated aqueous sodium hydroxide solution. The mixture was filtered and the filtrate was concentrated to dryness. The residue was recrystallized from Skellysolve B to give 2.9 g. (74% yield) of 5 methoxy 3 (1 methyl 2- pyrrolidinyl)indole free base; M.P. 118-1205 C.

Ultraviolet spectrum (ethanol) showed kmax, 275 (6,150); 295 (5,150).

Anulysis.-Calcd. for C H N O: C, 73.01; H, 7.87; N, 12.16. Found: C, 72.74; H, 7.73; N, 12.38.

In the same manner as shown above, 5,6 dimethoxy- 3 (1 methyl 2 pyrrolidinyl)indole free base, 5- ethoxy 2 methyl 3 (l-rnethyl 2 pyrrolidinyl) indole free base, 5 propoxy 3(l-methyl-Z-pyrrolidinyl) indole free base, and 6 butoxy 3 (.1-methyl-2-pyrrolidinyl)indole free base were prepared by substituting 5,6 dimethoxy 3 (l-methyl 2 pyrrolidinylidene) 3H-indole, 5 ethoxy 2 methyl 3 (1 methyl-2- pyrrolidinylidene)-3H-indole, 5 propoxy 3 (l-methyl- 2 pyrrolidinylidene)-3H-indole, and 6 butoxy 3 (1- methyl 2 pyrrolidinylidene)-3 H-indole, respectively, for

5 -methoxy-3 1-rnethyl-2-pyrrolidinylidene)-3H-indole.

EXAMPLE 33 .3 l-BENZYL-Z-PYRROLIDINYI.)

INDOLE FREE BASE A. 3-(I-benzyl-2-pyrr0lidinylidene)-3H-ind0le C. After the addition was complete the mixture was stirred 28 for 20 minutes and a solution of 28 g. (0.19 mole) of indole in 40 ml. of l-benzyl-Z-pyrrolidone was added dropwise, keeping the temperature below 27 C. The mixture was then heated at 80 C. for 1 hour, cooled, and ice was added. The solid mass was heated with three SOO-ml. portions of water and the mixture was poured into a 2 l. beaker. The aqueous solution was extracted with ether and made basic with g. of sodium hydroxide. The mixture was filtered and the solid was thoroughly washed with water and recrystallized twice from benzene (1 liter for each recrystallization) to yield 29.4 g. (50% yield) of 3-(1 benzyl 2 pyrrolidinylidene)-3H-indole;-

B. 3-(1-benzyl-2-pyrrolidinyl)indole free base A 19.2 g. (0.07 mole) quantity of 3 (1 benzyl-Z- pyrrolidinylidene)-3H-indole was slowly added as a solid to a mixture of 10.0 g. of lithium aluminum hydride and 400 ml. of tetrahydrofuran. The reaction mixture was refluxed for 4 hours, cooled, and decomposed with wet ether, followed by water and concentrated aqueous sodium hydroxide solution. The mixture was filtered and the filtrate was concentrated under reduced pressure to yield 15.0 g. (77% yield) of 3 (1benzyl-2-pyrrolidinyl)indole free base after recrystallization from Skelly solve B; M.P. 9l.593 C.

Ultraviolet spectrum (ethanol) showed k (38,950); sh 274 (5,850); 281 (7,300); 289 (5,450).

Analysis.Cal-cd. for C I-1 F1 1 C, 82.56; H, 7.29; N,

10.14. Found: C, 82,28; H, 7.36; N, 10.31.

A stirred solution of 5.74 g. (28.7 rnillimoles) of 3- (l-methyl 2 4 pyrrolidinyl)indole in 25 ml. of acetic acid was cooled to 10 C. and treated dropwise with a solution of 4.3 ml. of nitric acid (density 1.37) in 10 ml. of acetic acid. The temperature of the reaction mixture remained at 5-10 C. during the addition and was kept at 10 C. for an additional hour. The mixture was then allowed to warm to 25 C. and stand for 11 hours. The resulting dark solution was concentrated in vacuo under nitrogen and the residue was poured into ice-water. A water insoluble tar was absorbed on activated carbon and the solution was filtered through diatornaceous earth The residue was extracted with warm water, and the combined aqueous filtrate (about 400 ml.) was made ammonical and extracted with ether. The ether extract was washed with saturated salt solution, dried over anhydrous sodium sulfate, and concentrated. Crystallization of the residue from methanol-water yielded 1.375 55.,

M.P. l54.155 C., was prepared by recrystallization from v methanol-water.

Analysis.Calcd. for C H O N C, 63.66; H, 6.16;

N, 17.13. Found: C, 63.99; H, 6.20; N, 16.71.

The 6-nitro-3-(1-methyl 2 pyrrolidinyl)indole free base was reduced with lithium aluminum hydride to produce 6-amino-3-(l-methyl-Z-pyrrolidinyl)indole free base.

EXAMPLES 35.5 CHLORO 3 -(1 METHYL-2 PYRROLID INYLHNDOLE FREE BASE A. 5-chl r0-3- (1-metlzyI-Z-pyrrolidinylidene) -3H-in'dole Phosphorus oxychloride (40.8 g.; 0.26 mole) was added with stirring to 50 ml. (0.5 mole) of 1-methyl-2-pyrrolidone cooled in an ice bath at such a rate (25 minutes) that the temperature of the reaction mixture did not exceed 15 C. The yellow paste was stirred an additional 10 minutes while cooled in the ice bath. To this material was added with stirring a solution of 9.6 g. (0.063 mole) of -chloroindole in 50 ml. of 1-methyl-2-pyrrolidone during minutes. The brown solution was heated at 90 C. for 2 hours. The green solution was treated with 800 ml. of water, giving a yellow solution. The solution was basified by addition of a solution of 60 g. of sodium hydroxide in 300 ml. of water. The resulting yellow paste was filtered and washed with water. The solid Was crystallized from aqueous methanol (charcoal) giving 11.2 g. (76% yield) of yellow-brown crystals, M.P. 209211 C. (dec.) (sint. 201 C.). A portion was recrystallized twice from aqueous methanol, giving pale yellow needles of 5 chloro-3-(1-methyl-Z-pyrrolidinylidene)-3H-indole, M.P. 219221 C. (dec.) (sint. 212 C.).

Analysis.-Calcd. for C H ClN C, 67.10; H, 5.63; Cl, 15.23; N, 12.04. Found: C, 67.11; H, 5.55; Cl, 15.48; N, 11.74.

B. 5-chloro3-(1-metlzyl-2-pyrr0lidinyl) indole free base A mixture of 23 g. of 5-chlor03-(l-methyl-Z-pyrrolidinylidene)-3H-indole, 12 g. of sodium borohydride and 250 ml. of absolute ethanol was allowed to stand for 12 hours at 250 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 300 ml. of water. A solid separated. The mixture was extracted with two 300-ml. portions of ether. The combined ether extracts were washed with two 100-ml. portions of water and dried over anhydrous magnesium sulfate (charcoal). The ether was evaporated and the residue was crystallized from ether-Skellysolve B, giving 18.3 g. (79% yield) of ivory prisms, M.P. 139.5141 C. (sint. 135 C.). Recrystallization from ether-Skellysolve B (charcoal) gave 15.6 g. of nearly colorless prisms, M.P. 142144 C. Recrystallization from ether-Skellysolve B gave Colorless prisms of 5-chl0ro-3-(1-methyl-2-pyrrolidinyUindole free base, M.P. 143144.5 C.

Ultraviolet spectrum (ethanol) showed a 226 (35,150); sh 283 (5,200); 289 (5,500); sh 297 (4,250).

Analysis.-Calcd. for C H ClN C, 66.53; H, 6.44; Cl, 15.11; N, 11.94. Found: C, 66.55; H, 6.64; Cl, 15.16; N, 12.17.

EXAMPLE 36-5 FLUORO3-(1-METHYL-2-PYR- ROLIDINYL)INDOLE FREE BASE A. 5-flztor0-3- (1-methyl-Z-pyrrolidinylidene) -3H-ind0le Phosphorus oxychloride (40.8 g.; 0.26 mole) was added with stirring to 40 ml. (0.4 mole) of 1-methyl-2-pyrrolidone cooled in an ice bath at such a rate (25 minutes) that the temperature of the reaction mixture did not exceed 15 C. The yellow paste was stirred an additional 10 minutes while cooled in the ice bath. To this material was added a solution of 18.9 g. (0.14 mole) of S-fluoroindole in 60 ml. (0.6 mole) of l-methyl-Z-pyrrolidone at such a rate (25 minutes) that the temperature of the reaction mixture did not exceed 30 C. The resulting yellow solution which contained some solid was then heated at 95 C. for 2% hours. More solid formed during this time. The reaction mixture was treated with 800 ml. of water, giving an orange solution. The solution was basified with a solution of 60 g. of sodium hydroxide in 300 ml. of water. The solid which separated was collected by filtration and washed with water. Crystallization from aqueous methanol gave 21 g. (69% yield) of ivory solid, M.P. 207209 C. (dec.) (sint. 201 C.). Two recrystallizations from aqueous methanol afforded ivory needles of 5- fiuoro 3 (1 methtyl-2-pyrrolidinylidene)-3H-indole, M.P. 211-213 C. (-dec.) (sint. 205 C.).

Analysis.-Calcd. for C H FN C, 72.19; H, 6.06; N, 12.95. Found: C, 71.92; H, 6.14; N, 12.66

A mixture of 16 g. of 5-fiuoro-3-(l-methyl-Z-pyrrolidinylidene)-3H-indole, 8 g. of sodium borohydride, and 300 ml. of absolute ethanol was allowed to stand for 12 30 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 200 ml. of water. The mixture was extracted with 800 ml. of ether. The ether extract was washed with two 200-ml. portions of water and dried over anhydrous magnesium sulfate. The ether solution was evaporated to 250 ml. The evaporation was continued while Skellysolve B was added to keep the volume at 250 ml. until crystals formed. Cooling gave 14.2 g. (88% yield) of pale yellow prisms, M.P. 140443 C. Recrystallization from acetone- Skellysolve B afforded colorless prisms of 5-fluoro-3-(1- methyl-Z-pyrrolidinyl)indole free base, M.P. 142 143.5 C.

Ultraviolet spectrum (ethanol) showed A 218 (24,950); sh 276 (6,500); 285 (6,800); sh 296 (4,850). AnaIysis.-Calcd. for C H FN C, 71.52; H, 6.93; N, 12.84. Found: C, 71.63; H, 7.02; N, 12.80.

EXAMPLE 37.5 BENZYLOXY 3-(l-METHYL-2- PYRROLIDINYLHNDOLE FREE BASE A. 5 -benzyI0xy-3-(I -methyl-2-pyrr0lidinylidene)- 3H-ind0le Phosphorous oxychloride (40.8 g.; 0.26 mole) was added with stirring to 60 ml. (0.6 mole) of 1-methyl-2- pyrrolidone cooled in an ice bath at such a rate (20 minutes) that the temperature of the reaction mixture did not exceed 15 C. The yellow paste was stirred an additional 10 minutes While cooled in the ice bath. To this material was added with stirring a solution of 53.5 g. (0.24 mole) of S-benzyloxyindole in 150 ml. (1.5 moles) of 1- methyl-Z-pyrrolido-ne at such a rate (45 minutes) that the temperature of the reaction mixture did not exceed 15 C. The resulting thick paste was heated at C. for 2 hours. After cooling somewhat the mixture was dissolved in 750 ml. of water and the Warm solution was filtered from a small amount of insoluble solid. The filtrate upon cooling deposited a solid. The mixture was basified by the addition of a solution of 60 g. of sodium hydroxide in 300 m1. of water. The thick paste obtained was diluted with one liter of water and filtered. The solid was washed with 500 ml. of water. The solid was crystallized from aqueous methanol (charcoal), giving 65.4 g. (90% yield) of buff crystals, M.P. 147150 C. (sint. 142 C.). A portion was recrystallized from actone-Skellysolve B (charcoal), giving pale yellow needles, M.P. 148-151 C. (sint. 144 C.). Recrystallization from acetone-Skellysolve B atforded pale yellow needles of 5-benzyloxy-3(1- methyl-2-pyrr0lidinylidene)-3Hindole, M.P. 149152 C. (sint. 147 C.).

Ultraviolet spectrum (ethanol) showed A 211 (31,100); 252 (11,750); 257 (13,050); 281 (11,750); 286 (12,050); 336 (15,050).

Analysis.Calcd. for C H N O; C, 78.90; H, 6.62; N, 9.20. Found: C, 78.06; H, 6.79; N, 9.11.

In the same manner as shown above,

5 p-methoxybenzyloxy -2-ethyl-3- l-methyl-Z- pyrrolidinylidene -3H-in dole, 5- p-ethoxybenzyloxy -3-( 1-methyl-2-pyrrolidinylidene)-3H-indole, 5- (p-propoxybenzyloxy) -3 l-methyl-Z- pyrrolidinylidene -3H-indole, and 7- p-butoxybenzyloxy) -3- l-methyl-Z-pyrrolidinylidene)-3H-indole were prepared by substituting 5- p-methoxybenzyloxy -2-ethylindole, 5-(p-ethoxybenzyloxy)indole, 5 p-propoxybenzyloxy) -indole, and 7-(p-butoxybenzyloxy)indole, respectively, for S-benzyloxyindole.

B. 5-benzyl0xy-3-(Z-mellzyZ-2-pyrr0lidinyl)indole free base A mixture of 15 g. of 5-benzy1oxy-3(l-methyl-Z-pyrrolidinylidene)-3H-indole, 150 ml. of ethanol, and 0.2 g. of platinum oxide catalyst was shaken on a Parr apparatus at 50 lbs. initial hydrogen pressure. After 6 /2 hours one equivalent of hydrogen was absorbed. The catalyst was removed by filtration and the solvent was removed under reduced pressure on the steam bath. The residual brown oil was dissolved in 500 ml. of ether. The ether solution was extracted with two 100-ml. portions of 1 N sodium hydroxide, washed with two 100-rnl. portions of water and dried over anhydrous magnesium sulfate (charcoal). Most of the ether was evaporated and 200 ml. of Skellysolve B was added while keeping the solution boiling. Cooling produced 11.7 g. (77.5% yield) of ivory prisms of -benzyloxy-3-(1-methyl-2- pyrro1idinyl)indole free base, M.P. l24-126 C.

Ultraviolet spectrum (ethanol) showed 1 sh 222 (29,500); sh 260 (4,050); 276 (6,650); 295.5 (5,300); sh. 308 (3,500).

Analysis.-Calcd. for C H N O: C, 78.40; H, 7.24;

N, 9.15. Found: C, 78.34; H, 6.97; N, 9.16.

In the same manner as shown above,

' 5- (p-ethoxybenzyloxy -3-( l-methyl-Z-pyrrolidinylidene)-3H-indole,

5- (p-propoxybenzyloxy -3-( l-methybZ-pyrrolidinylidene -3H-indole, and

7- (p-butoxybenzyloxy) -3- 1-methyl-2-pyrrolidinylidene)-3-H-indole, respectively, for

5-benZyloxy-3-( 1-rnethyI-Z-pyrrolidinylidene) -3H- indole.

EXAMPLE 3 8 .5 -TYDROXY-3-( l-M ETHYL-2- PYRROLIDTNYL) INDOLE FREE BASE A mixture of 12.2 g. of 5-benZyloxy-3-(1-methyl-2- pyrrolidinyl)indole free base, 150 ml. of absolute ethanol, and 0.5 g. of 10% palladium-on-charcoal catalyst was shaken on 'a Parr apparatus at 50 lbs. initial hydrogen pressure. After 4 hours one equivalent of hydrogen was absorbed. The catalyst was removed by filtration and the solvent was removed under reduced pressure on the steam'bath. The residual oil was shaken with 300 ml. of ether. The ether solutionwas decanted from a small amount of tarry material. Crystals soon began forming in the ether solution. The ether was evaporated while being replaced with 100 ml. of acetone. While keeping the solution boiling, 300 ml. of Skellysolve B Was added. Cooling produced 5.2 g. (60.5% yield) of buff crystals, M.P. 15916l C. (sint. 155 C.). Two recrystallizations from acetone-Skellysolve B (once with charcoal treatment) afforded buff crystals of 5-hydroxy-3-(1-metl1yl- 2-pyrrolidinyl)indole free base, MP. 161-163 C. (sint. 7

. Analysis.-Calcd. for C H N O: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.17; H, 7.63; N, 12.47.

EXAMPLE 39.6-BENZYLOXY-3-( l-METHYIJ-Z- PYRROLIDINYLHNDOLE FREE BASE A. 6-benzyloay-3 (1-merhyZ-Z-pyrroiidinylidene)-3H- indole Phosphorus oxychloride (40.8 g.; 0.26 mole) was added with stirirng to 50 ml. (0.5 mole) of l-methyl-Z- pyrrolidone cooled in an ice bath at such a rate (25 minutes) that the temperature of the reaction mixture did not exceed 15 C. The yellow paste was stirredan additional 10 minutes while cooled in the ice bath. To this material was added with stirring a solution of 10 (0.043 mole) of 6-benzyloxyindole in ml. (0.5 mole) of.l-methyLZ-pyrrolidone during 15 minutes. The temperature did not exceed 10 C. The orange solution was then heated at 80 C. for 2 hours. The green solution was treated with 500 ml. of Water, giving an orange solution. The solution was basified with a solution of g. of sodium hydroxide in 300 ml. of water. The solid which separated was collected by filtration and washed with water. Crystallization from aqueous methanol gave 12 g. (88% yield) of buff solid, MP. 180184 C. (dee). Two recrystallizations from aqueous methanol afforded buff crystals of 6-benzyloxy-3-(1-methyl-2-pyrrolidinylidene)-3H-indole, MP. ISO-184 C. (dee).

Ultraviolet spectrum (ethanol) showed A 2 14 (34,900); 244 (13,500); sh 248 (13,050); 284 (15,500); 348 (13,900).

Analysis.-Calcd. for C H N O: C, 78.90; H, 6.62; N, 9.20. Found: C, 78.23; H, 6.76; N, 8.89.

B. 5-benzyl0xy-3-(1-methyI-Z-pyrrclia'inyl) indole free base a A mixture of 10.6 g. of 6-benzyloxy-3-(1-methyl-2- pyrrolidinylidene)-3H-indole, 10 g. of sodium borohydride, and 500 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. The solvent was removed under reduced pressure on tlre'steam bath. The residue was treated with 400 ml. of water. The mixture was extracted with two 400-ml. portions of ether. The combined ether extracts were washed with three ZOO-ml. portions of water, treated with charcoal, and dried over anhydrous magnesium sulfate. The ether solution was concentrated, Skellysolve B was added, and the solution was concentrated further. Cooling produced 9.1 g. (85% yield) of ivory prisms, MP. ll7.5-1l8.5 C. (sint. 115 C.). Two recrystallizations from acetone-Skellysolve B afforded ivory prisms of 6-benzyloxy-3-(l-methyl-2-pyrrolidinyl)indole free base, M.P. 118119 C. (sint. 116 C.).

Ultraviolet spectrum (ethanol) showed A 222 (40,500); 264 (4,450); 271 (4,650); 292 (5,400).

Analysis.-Calcd. for C H N O: C, 78.40; H, 7.24;

V N, 9.15. Found: c, 78.07; H, 7.07; N, 9.19.

EXAMPLE 40.-6-HYDROXY-3-( l-METHYL-Z-PYR- ROLTDINYL INDOLE HYDROCHLORIDE A soluti0n2 g. of 6-benzyloxy-3-(1-methyl-2-pyrrolidinyl)indole free base (Example 39) in ml. of anhydrous ether was treated with ethereal hydrogen chloride. The solid which precipitated was filtered and washed.

with ether, giving 2.2 g. of colorless 6-benZyloxy-3-(1- methyl-Z-pyyrolidinyl)indole hydrochloride, MP. 111 C. (sint. 100 C.). A mixture of 2 g. of the hydrochloride, 0.2 g. of 10% palladium-on-charcoal catalyst, and 50 ml. of absolute ethanol was shaken'on a Parr apparatus at 51.5 lbs. initial hydrogen pressure. After 6 hours one equivalent of hydrogen had been absorbed. The catalyst was removed by filtration and the solvent was removed under reduced pressure on the steam bath. The residue was crystallized from'methanolether, giving a sticky solid. The filtration 'was diluted with ether and cooled to give crystals, which after drying weighed 0.22 g. and melted between 193195 C. (prior sintering); Recrystallization from methanol-isopropanol-ether .gave 6- l1ydroxy-3-( l-methyl-2-pyrrolidinyl)indole hydrochloride as ivory needles, which after drying weighed 0.21 g. and melted between 193195 C. (sint. 190 C.), An analytical sample was prepared by drying for 12 hours at C. under reduced pressure.

Ultraviolet spectrum (ethanol) showed k 215 (30,050); sh 254"(2,750); sh 262 (3,750); 270 (4,250);

A. 7-methyl-3-(1-benzyl-2-pyrrolidinylidene)-3H-ind0le hemz'hydrate Phosphorus oxychloride (20.4 g.; 0.13 mole) was added with stirring during 25 minutes to 30 g. (0.171 mole) of l-benzyl-Z-pyrrolidone cooled in an ice bath. The temperature remained below 10 C. The orange paste was stirred an additional 10 minutes while cooled in the ice bath. To this material was added with stirring a solution of 15.8 g. (0.12 mole) of 7-methylindole in 40 g. (0.228 mole) of 1-benzyl-2-pyrrolidone during 48 minutes. The temperature did not exceed 20 C. The orange solution was heated at 80 C. for 1 hour. The red solution was poured into 1000 ml. of water, causing an oil to separate. The mixture was heated almost to boiling and then cooled in an ice bath. The solid which separated was collected by filtration and washed with ether. The solid was suspended in 1500 ml. of water and basified by the addition of aqueous sodium hydroxide solution. The solid was collected by filtration, washed with water, and crystallized from aqueous methanol, giving 33.5 g. (97% yield) of yellow needles of 7-methyl-3-(l-benzyl-Z-pyrrolidinylidene)-3H-indole hemihydrate, M.P. 172-174 C. (dec.) (sint. 167 C.).

Analysis.Calcd. for C H N /2H O: C, 80.75; H, 7.12; N, 9.42. Found: C, 80.55; H, 7.20; N, 9.91.

B. 7-methyl-3-(1-benzyl-Z-pyrrolidinyl) indole free base A mixture of 31.4 g. of 7-methyl-3-(1-benzyl-2-pyrrolidinylidene)-3H-indole hemihydrate, 15 g. of sodium borohydride, and 500 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 200 ml. of water. The mixture was extracted with two 400-ml. portions of ether. The ether extracts were washed with three 200-ml. portions of water and dried over anhydrous magnesium sulfate. The ether was evaporated. The residual oil was crystallized twice from ether-Skellysolve 13, giving 22.7 g. (74% yield) of ivory prisms, M.P. 95-98 C. Recrystallization from ether-Skellysolve B afiorded pale pink prisms of 7-methyl- 3-(l-benzyl-Z-pyrrolidinyl)indole free base, M.P. 95- 98 C.

Ultraviolet spectrum (ethanol) showed Amax, 220 (42,550); sh 273 (6,550); 279 (6,650); 289 (5,250).

Analysis.Calcd. for C H N C, 82.72; H, 7.64; N, 9.65. Found: C, 82.44; H, 7.41; N, 9.63.

EXAMPLE 42.-BROMO-3-( 1-BENZYL-2-PYR- ROLIDINYLHNDOLE HYDROCHLORIDE A. 5 -bromo-3- 1 -benzy l-Z-pyrrolidiny Zidene -3H-ind0le Phosphorus oxychloride (20.4 g.; 0.13 mole) was added during 30 minutes with stirring to 40 g. (0.228 mole) of 1-benzy1-2-pyrrolidone cooled in an ice bath. The temperature remained below 10 C. The orange paste was stirred an additional 10 minutes while cooled in the ice bath. To this material was added wtih stirring a solution of 23.6. (0.12 mole) of 5-bromoindole in 60 g. (0.342 mole) of 1-benzyl-2-pyrrolidone during 20 minutes. The temperature did not rise above 12 C. The orange solution was heated at 80 C. for 1 hour. The red solution was poured into 1000 m1. of water, causing an oil to separate. The mixture was heated almost to boiling, cooled in an ice bath, and basified by the addition of aqueous sodium hydroxide solution. The orange solid which separated was collected by filtration and washed with water and then ether (about 200 ml.). Crystallization from 500 ml. of methanol gave 25.5 g. (60% yield) of colorless needles, M.P. 202 C. (dec.) (sint. 197 C.). A portion was recrystallized twice from aqueous methanol, affording colorless needles of 5-bromo-3-(1-benzyl-2-pyrrolidinlyidene)-3-H-indole, M.P. 202 C. (dec.) (sint. 197 C.).

34 Ultraviolet spectrum (ethanol) showed 1 215 (31,250); sh 248 (8,900); sh 252 (9,050); sh 258 (9,400); 280 (15,250); sh 286 (13,750); sh 300 (7,050); 350 (15,250).

Analysis.Calcd. for C H BrN z C, 64.59; H, 4.85. Found: C, 64.43; H, 4.61.

B. 5-br0m0-3-(1-benzyl-Z-pyrrolidinyl)indole hydrochloride A mixture of 23.7 g. of 5-brorno-3-(l-benzyl-Z-pyrrolidinylidene)-3H-indole, 12 g. of sodium borohydride, and 500 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 200 ml. of water. The mixture was extracted with two 400- ml. portions of ether. The ether extracts were washed with two 200-ml. portions of water and dried over anhydrous magnesium sulfate. The ether solution containing 5-bromo-3-(1-benzyl-2-pyrrolidinyl)indole free base was treated with ethereal hydrogen chloride. The solid was collected by filtration and crystallized from ethanol-ether, giving 19.6 g, (74% yield) of colorless prisms of 5-bromo-3-(1- benzyl-Z-pyrrolidinyl)indole hydrochloride, M.P. 181- 186 C.

Ultraviolet spectrum (ethanol) showed Amax, 220 (41,- 600); 279 (5,500); 287 (5,750); 296 (4,250).

Analysis.Calcd. for C H BrclN z C, 58.25; H, 5 .1 N, 7.15. Found: C, 58.55; H, 5.08; N, 6.79.

EXAMPLE 43 .5CHLORO-3-( l-BENZYL-2-PYR- ROLIDINYLHND OLE HYDROCHLORIDE A. 5-chl0r0-3- (1-benzyl-2-pyrr0lidinylidene)-3H-ind0le Phosphorus oxychloride (20.4 g.; 0.13 mole) was added during 25 minutes with stirring to 30 g. (0.171 mole) of 1-benZyl-2-pyrr0lidone cooled in an ice bath. The temperature remained below 10 C. The orange paste was stirred an additional 10 minutes while cooled in the ice bath. To this material was added with stirring a solution of 15.2 g. (0.1 mole) of 5-chloroindole in 28 g. (0.16 mole) of 1-benzyl-2-pyrrolidone during 15 minutes. The temperature did not rise above 10 C, The ice bath was replaced with a warm water bath. The temperature of the reaction mixture began rising rapidly and in 10 minutes reached a maximum of 75 C. The brown solution was then heated at 75 C. for 1 hour. The brown solution was poured into 1000 ml. of water, causing an oil to separate. The mixture was heated almost to boiling, cooled in an ice bath, and extracted with 500 ml. of ether. The aqueous layer, which contained an oil, was basified by the addition of aqueous sodium hydroxide solution. The solid which separated Was collected by filtration and washed with water. The solid was mixed with 5 00 ml. of boiling methanol. Cooling gave 24.6 g. (79% yield) of nearly colorless needles, M.P, 182 C. (dec.) (sint. 178 C.). A portion was recrystallized twice from aqueous methanol, affording colorless needles of 5-chloro-3-(l-benzyl-Z-pyrrolidinylidene)-3H-indole, M.P. C. (dec.) (sint. 181 C.).

Ultraviolet spectrum (ethanol) showed k 214 (29,450); sh 259 (8,750); 279 (16,200); sh 286 (14,000); 350 (17,800).

Analysis.-Caled. for C H C1N C, 73.90; H, 5.55; C1, 11.48; N, 9.07, Found: C, 73.60; H, 5.59; Cl, 11.38; N, 8.57.

In the same manner as shown above, 5-chloro-3-[l-(pmethoxybenzyl -2-pyrrolidinylidene] -3H-indole, 5 -chloro- 3-[l-(p-ethoxybenzyl)-2-pyrrolidinylidene]-3H-indole, 5- chloro-3-[1-(p-propoxybenzyl)-2-pyrrolidiny1idene] 3H- indole, and 5-chloro-3[l-(p-butoxybenzyl)-2-pyrrolidinylidene]-3H-indole were prepared by substituting l-(pmeth oxybenzyl -2-pyrrolidone, 1- p-ethoxybenzyl -2-pyrrolidone, 1-(p-propoxybenzyl)-2-pyrrolidone and 1(p-butoxybenzyl)-2-pyrrolidone, respectively, for 1-benzyl-2- pyrrolidone.

as B. -chl0r0-3-(1-benzyl-2-pyrrolidinyl)indole hydrochloride A mixture of 22.8 g. of 5-chloro-3-(1-benzyl-2-pyrrolidinylidene)-3H-indole, 11 g. of sodium borohydride, and 300 ml. of absolute ethanol was allowed to stand for 12 hours at 25 C. The solvent was removed under reduced pressure on the steam bath. The residue was treated with 200 ml. of water. The mixture was extracted with two 400-ml. portions of ether, The ether extracts were washed with two 200-ml. portions of water and dried over anhydrous magnesium sulfate. The ether was evaporated. The residual oil, 5-chloro-3-(1-benzyl-2-pyrrolidinyl)indole free base, was dissolved in 400 ml. of anhydrous ether and treated with ethereal hydrogen chloride. The solid was collected by filtration and crystallized from ethanol-ether, giving 19.4 g. (76% yield) of colorless prisms of S-chloro- 3-(1-benzyl-2-pyrrolidinyl)indole hydrochloride, M.P. 174-176 C. (sint. 170 C.).

Ultraviolet spectrum (ethanol) showed x 226 (37,850); sh 268 (4,950); 278 (5,650); 286 (5,800); 296 (4,300).

Analysis.Calcd. for C H Cl N C, 65.70; H, 5.81; Cl, 20.42; N, 8.07. Found: C, 65.44; N, 5.90; Cl, 20.42; N, 7.91.

In the same manner as shown above 5-chloro-3-[l-(pmethoxybenzyl)-2-pyrrolidinyl]indole hydrochloride, 5- chloro-3-[ 1- p-ethoxybenzyl) -2-pyrrolidinyl] indole hydrochloride, 5 -chloro-3- 1- (p-propoxybenzyl) 2-pyrrolidinyl] indole hydrochloride, and 5-chloro-3-[l-(p-butoxybenzyl)-2-pyrrolidinyl]indole hydrochloride were prepared by substituting 5-chloro-3-[l-(p-methoxybenzyl) 2 pyrrolidinylidene] -3 H-indole, 5 -chloro-3-[ 1- (p-ethoxybenzyl -2- pyrrolidinylidene] -3H-indole, 5 chloro-3-[l-(p-propoxybenzyl)-2-pyrrolidinylidene]-3H-indole, and 5-chloro3-[l- (p-butoxybenzyl -2-pyrrolidinylidene] -3H-indole, respectively, for 5-chloro-3-(1-benzyl-2-pyrrolidinylidene)-3H- indole.

EXAMPLE 44 .3- 1-METHYL-2-PYRROLIDINYL) INDOLE N-OXIDE A solution of 7.0 g. (0.035 mole) of 3-(l-methyl-3- pyrrolidinyl)indole free base, 4.7 ml. (0.04 mole) of 29% hydrogen peroxide, and 50 ml. of methanol was allowed to stand at 25 C. for three days. The solution was shaken with platinum oxide catalyst for two hours and filtered. The solution was taken to dryness under reduced pressure to yield a noncrystalline residue. The residue was extracted with hot Skellysolve B and decanted from colored material. The solution was refrigerated for 12 hours and decanted. The residue was twice dissolved in ethyl acetate, treated with decolorizing charcoal, and filtered. The filtrate was diluted with Skellysolve B until a guru precipitated. The solvent was decanted and the residue was dried at 3 mm. pressure to yield 1.7 g. of 3-(1- methyl-Z-pyrrolidinyl)indole N-oxide.

Ultraviolet spectrum (ethanol) showed X 217.5 37,300 272 5,930 sh 277.5 (6,080); 280 (6,100); 288 (5,370).

Analysis.Calcd for C E -N 0: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.16; H, 7.76; N, 12.77.

EXAMPLE 45 .-2-METHYL-3 l-METHYL-Z- PYRROLIDINYL)-INDOLE FREE BASE A. 2-methyl-3- (1-methyl-2-pyrr0lidinylidene -3H- indole hydrate Phosphorus oxychloride (81.6 g.; 0.52 mole) was added with stirring to 100 ml. (1.0 mole) of l-rnethyl-2- pyrrolidone cooled in an ice bath at such a rate (50 minutes) that the temperature of the reaction did not exceed 15 C. The thick yellow paste was stirred an additional 20 minutes while cooled in the ice bath. To this material was added with stirring during 105 minutes a solution of 63 g. (0.48 mole) of 2-methylindole in 100 ml. (0.1 mole) of l-methyl-Z-pyrrolidone. The temperature did not rise above 18 C. The ice bath was removed from the viscous brown liquid and in 20 minutes the temperature rose to 30 C. The mixture was heated at 80 C. for 2 hours. After cooling the viscous brown liquid was dissolved in 1500 ml. of water. A solution of 120 g. of sodium hydroxide in 600 ml. of water was added. The resulting paste was diluted with 800 ml. of water and filtered. The solid was washed with 900 ml. of water and dissolved in 1000 ml. of ethanol. The volume was reduced to 500 ml. and 750 ml. of water was added while keeping the solution boiling. The solid obtained on cooling was recrystallized from aqueous methanol, giving 108 g. (96% yield) of green needles, M.P. 123125 C. (dec.) (sint. 113 C.) A portion of this material was recrystallized once from aqueous methanol (charcoal) and then twice from aqueous methanol. The needles thus obtained were washed with methanol which removed most of the colored material, giving but]? needles of 2-methyl- 3-(l-methyl-2-pyrrolidinylidene) 3H indole hydrate, M.P. 123-125 C. (dec.) (sint. 120 C.).

Analysis.-Calcd for C 4H N -H O: C, 73.01; H, 7.88; N, 12.17. Found: C, 72.40; H, 7.72; N, 12.17.

In the same manner as shown above, S-benzyloxy-Z- ethyl-3-(1-methyl-2-pyrrolidinylidene) 3H indole hydrate, 2-propyl-3-(1-methyl-2-pyrrolidinylidene)-3H indole hydrate, and 2-butyl-3-(1-methyl 2 pyrrolidinylidene)-3H-indole hydrate were prepared by substituting 5-benzyloxy-2-ethylindole, 2-propylindole, and 2-butylindole, respectively, for Z-methylindole.

B. 2-me thyl-3-(1-methyZ-Z-pyrrolidinyl)indole free base A mixture of 20 g. of 2-methyl-3-(1-methyl-2-pyrrolidinylidene)-3H-indole hydrate, 150 ml. of methanol, and 0.5 g. of 5% palladium-on-charcoal catalyst was shaken on a Parr apparatus at lbs. initial hydrogen pressure. After 48 hours one equivalent of hydrogen was absorbed.

- The mixture was filtered and the filter cake was washed with 50 ml. of methanol. The methanol was removed under reduced pressure on the steam bath. The residue was treated with 800 ml. of ether, slurried with charcoal and diatomaceous earth, and filtered. The filtrate was reduced to 200 ml. on the steam bath which caused a solid to separate. Skellysolve B ml.) was added. Filtration yielded 2.3 g. ofunchanged starting material. The filtrate was evaporated to dryness. The residue was crystallized from Skellysolve B, giving 11 g. (59% yield) of yellow-brown solid, M.P. -122 C. (sint. 116 C.). Recrystallization from Skellysolve B (charcoal) and then from ether-Skellysolve B gave yellow prisms of Z-methyl- 3-221-methyl-2-pyrrolidinyl)indole free base, M.P. 122- Ultraviolet spectrum (ethanol) showed A 221 (35,500); sh 275 (6,700); 281 (7,000); 288 (5,900).

Analysis.Calcd for C H N C, 78.46; H, 8.46; N, 13.08. Found: C, 78.80; H, 8.30; N, 12.97.

In the same manner as shown above, 5-benzyloxy-2- ethyl-3-(1-methyl 2 pyrrolidinyl)indole free base, 2- propyl-3-(l-methyl-Z-pyrrolidinyl)indole free base, and 2-butyl-3( 1-methyl-2-pyrrolidinyl)indole free base were prepared by substituting 5-benzyloxy-2-ethyl-3-(l-methyl-2-pyrrolidinylidene)-3H-indole hydrate, 2-propyl-3-(1- methyl-2-pyrrolidinylidene)-3H-indole hydrate, and 2- butyl-3: 1-methyl-2-pyrrolidinylidene) -3H-indole hydrate, respectively, for 2-methyl-3-(1-rnethyl 2 pyrrolidinylidene)-3H-indole hydrate.

EXAMPLE 46.3-(1-PROPYL-5,5-DIMETHYL-2- PYRROLIDINYL) INDOLE FREE BASE A. 3-(5,S-dimethyZ-Z-pyrolidinylidene)-3H-in'd0le hydroiodide A solution of 3-(5,5-dimethyl-1-pyrrolin-2-yl)indole (Example 22, Part B) (2.1 g.; 0.01 mole) in 25 ml. of methanol and 5 ml. of methyl iodide was refluxed for 4 hrs. The resulting suspension was evaporated to dryness and the residue was crystallized from ethanol to give 1.56 g. (46% yield) of 3-(5,5-dimethyl-Z-pyrrdlidinylidene)a B. 3-(5,5-dimethyl-2-pyrrolidinyl) indole hydrochloride Sodium borohydride (1.3 g.) was added to a solution of 3-(5,S-dirnethyl-Z-pyrrolidinylidene) 3H indole hydroiodide (1.26 g.; 3.7 millimoles) in 100 ml. of ethanol. The mixture was stirred for 4 hrs. and allowed to stand for 72 hours. It was evaporated to dryness in vacuo, 50 ml. of Water was added, and extraction was performed with ether. The extract was washed with saturated salt solution and evaporated to give 0.8 g. of an oil, 3-(5,5- dimethyl-2-pyrrolidinyl)indole free base. A solution of this oil in ether was converted to the hydrochloride with ethereal hydrogen chloride and the resulting solid was crystallized from methanol-ether to give 0.5 g. of 3-(5,5- dimethyl 2 pyrrolidinyl)indole hydrochloride (54% yield), M.P. 230-231 C.

C. 3-(1-pr0pyl-5,5-dimethyl-Z-pyrrolidinyl)indole free base The 3-(5,5-dimethyl-2-pyrrolidinyl)indole hydrochloride (Part B) was dissolved in 10 ml. of water and the solution was basified with 15% aqueous sodium hydroxide solution and extracted with ether. The extract was washed with saturated salt solution, dried over anhydrous sodium sulfate, and evaporated to give 3-(5,5-dimethyl-2-pyrrolidinyl)indole free base. In the same manner as shown in Example 22, Parts D and E, 3-( 1-propy1-5,5-dimethyl- 2-pyrrolidinyl) indole free base was prepared by substituting propionic anhydride for acetic anhydride.

EXAMPLE 47.7-ETHOXY-3-( 1,4-DIPROPYL-2- PYRROLIDINYLHNDOLE FREE BASE In the same manner as shown in Example 32, 7-ethoxy- 3-(1,4-dipropyl-2-pyrrolidinyl)indole free base was prepared by substituting 7-ethoxyindole and 1,4-dipropyl2- pyrrolidone for 5-methoxyindole and 1-methyl-2-pyrrolidone to produce 7-ethoxy-3-(1,4-dipropyl-2-pyrrolidinylidene)-3H-indole and reducing the latter with lithium aluminum hydride.

The 3- (2-piperidyl)indoles prepared by the novel process of the present invention are useful oxytocics.

The 3-(2-pyrrolidinyl)indoles of the present invention are orally and parenterally active in birds, animals, mammals and humans for the treatment of neuroses, such as anxiety, tension, apprehension, or agitation, and for treatment of psychotic conditions, e.g., in schizophrenia.

In the classical avoidance test, the compounds of the present invention demonstrated the ability to relieve experimentally-induced anxiety. The method of Verhave et al., Arch. Int. Pharmacodyn. 116, 45, 195 8, was employed. Rat data are shown in Table I and a comparison is made to prior art compounds.

TABLE 1 Rating Index: ++=above 90; =030) Compound: Rating 3-(1-methyl-2-pyrrolidinyl)indole free base 7 methyl 3-( 1 methyl-Z-pyrrolidinyl)indole free base 3 1,5 dimethyl 2 pyrrolidinyl)indole free base In the fighting-mouse test, the 3-(2-pyrrolidinyl)indoles of the present invention demonstrated the ability to minimize aggressive behavior in mice in which an aggressive behavior had been induced as a result of isolation stress. The method of Yen et al., Phormacologist 4, 173, 1962, was employed. Groups of six mice were injected with a maximum of 50 mg./kg. Tests were carried out sixty minutes after administration and doses Were decreased in 0.3 log intervals. The ED is the drug dosage which prevented 50 percent of the animals from continuing their aggressive behavior (Table II).

TABLE 11 Compound: ED (mg./ kg.)

7 methyl 3 (l methyl 2 pyrrolidinyDindole free base 8 1 methyl 3 (1 methyl 2 pyrrolidinyDindole free base 9 4 chloro 3 (l methyl 2 pyrrolidinyl)indole free base 9 5 fiuoro 3 (l methyl 2 pyrrolidinyDindole free base 9 3 (1 ethyl 2 pyrrolidinyl)indo1e hydrochloride 11 5 chloro 3 (1 methyl 2 pyrrolidinyl)indole free base 11 2 methyl 3 (1 methyl 2 pyrrolidinyl)indole free base 11 The 3-(2-pyrrolidinylinddoles, 3-(1-pyrrolin 2 yl)indoles, and 3-(2-pyrrolidinyldene)-3H-indoles of the present invention have also demonstrated pseudocholinesterase inhibitory activity which is a valuable tool in producing selective stimulation and lucid intervals in confused mental states. Inhibition of this enzyme is determined manometrically using human serum as the enzyme source and acetylcholine chloride (10' molar) as the substrate. The I (Table III) is that concentration of test compound which produces 50% inhibition of the enxyme. Compounds producing less than 50% inhibition at a 10 molar concentration of the test compound are considered inactive.

The novel 3-(2-pyrrolidinyl)indoles, 3-(1-pyrrolin-2- yl)indoles, and 3-(2-pyrrolidinylidene)-3-H-indoles of the present invention are also useful antianaphylactic agents and anti-inflarnmatory agents. For example, utilizing the foot paw edema test, 7-methyl-3-(1-methyl-2-pyrrolidinyl)indole free base, 3-(1,3-dimethyl-Z-pyrrolidinyl) indole hydrochloride and 3-(1-pyrrolin-2-yl)indole are 2.8, 2.1, and 1.0, respectively, as active as phenylbutazone.

The novel 3-(2-pyrrolidinyl)indoles of the present invention are also useful as anorexigenic agents.

For the purposes noted above, compositions are prepared in solid and liquid unit dosage forms, such as tablets, capsules, powders, granules, syrups, elixirs, and

39 the like, containing suitable quantities of the compounds of the present invention.

Powders are prepared by comminuting the active ingredient to a suitable fine size and mixing with a similarly comminuted diluent. The diluent can be an edible carbohydrate material such as starch. Advantageously, a sweetening agent is present as well as a flavoring agent. Dry granulations for reconstitution with water are prepared utilizing water-soluble diluents. A powder mixture of finely divided active ingredient and a water-soluble diluent such as sucrose, glucose, and the like is wetted with a binder such as acacia mucilage or gelatin solution and forced through a screen to form granules which are allowed to dry. Advantageously, a thickening or suspending agent such as methylcellulose is present as well as a wetting agent and flavoring agent.

Capsules are produced by preparing a powder mixture as hereinbefore described and filling into formed gelatin sheets. Advantageously, as an adjuvant to the filling operation, a lubricant such as talc, magnesium stearate, and calcium stearate is added to the powder mixture before the filling operation.

Tablets are made by preparing a powder mixture,

granulating or slugging, adding a lubricant and pressing into tablets. The powder mixture is prepared by mixing the active ingredient suitably comminuted, with a diluent or base such as starch, lactose, kaolin, dicalcium phosphate, and the like. The powder mixture can be granulated by wetting with a binder such as corn syrup, gelatinsolution, methylcellulose solution, or acacia mucilage and forcing through a screen. As an alternative to granulating, the powder mixture can be slugged, i.e., run through a tablet machine and the resulting imperfectlyformed tablets broken into pieces (slugs). The slugs can be lubricated to prevent sticking to the tablet-forming dies by meansof the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.

Advantageously, the tablet can be provided with a protective coating consisting of a sealing coat of shellac, a coating of sugar and methylcellulose, and a polish coating of carnauba wax. I

Oral fluids are prepared in unit dosage forms such as syrups and elixirs wherein each teaspoonful of composition contains a predetermined amount of active ingredient for administration.

A syrup is prepared by dispersing the active ingredient in a suitably-flavored aqueous sucrose solution. Similarly an elixir is prepared utilizing a hydro-alcoholic vehicle. Elixirs are advantageous vehicles for use when another therapeutic agent, which is not sufficiently watersoluble, is to be included in the composition.

For parenteral administration aqueous fluid unit dosage forms can be prepared. In preparing the parenteral form, a measured amount of active ingredient is placed in a vial, and the vial and its contents are sterilized and sealed. An accompanying vial of stearile water is provided as a vehicle to form a suspension prior to administration. Advantageously, the sterile water can have dissolved therein a local anesthetic and a buffering agent. Parenteral aqueous solutions can be made by preparing a suitable pharmaceutically-acceptable salt of the active ingredient such as the acetate, citrate, tartrate, maleate, lactate, and the like.

Alternatively, a parenteral suspension can be prepared by suspending the active ingredient in a parenterally-acceptable vegetable oil with or without additional adjuvants, and sterilizing after filling into vials.

For veterinary oral use the active ingredient is conveniently prepared in the form of a food premix. The food premix can comprise the active. ingredient in admixture with an edible pharmaceutical diluent of the type previously mentioned such as starch, oatmeal, flour, calcium carbonate, talc, dried fish meal, and the like. The prepared premix is then conveniently added to the regular feed, thereby providing medication to the animal in the course of feeding.

The term unit dosage form as used in the specification and claims refers to physically discrete units suitable as unitary dosage for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active material for therapeutic use in humans and animals, as disclosed in detail in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills, troches, powder packets, granules, wafers, cachets, segregated multiples of any of the foregoing, and other forms as herein described.

In addition to the administration of a compound of this invention as the principal active ingredient of compositions for the treatment of the conditions noted above, the said compound can be included with other types of compounds to obtain advantageous combinations of properties. Such combinations can include the compounds of this invention in combination with analgetic agents such as codeine, aspirin, acetophenetidin, salicylamide and N- acetyl-p-aminophenol; hypnotic agents such as the barbiturates and chloral hydrate; steroids such as hydrocortisone, prednisolone, fluprednisolone, and methylprednisolone; and muscle relaxants such as chlorzoxazone, corisoprodol, mephenesin, meprobarnate, phenaglycodol, and zoxazolamine; and antihistamines such as chlorpheniramine maleate, p-rophenpyr idamine maleate, and pyrilamine.

The amount of active ingredient that is to be administered depends on the age, weight of the patient, the particular condition to be treated, the frequency of admini stration, and the route of administration. The dose range is from about 0.15 to about 15 mg. per kg. of body weight or a total dose for humans of from about 10 to about 1000 mg. given as a single dose, with the preferred range from about 25 to 500 mg.

Veterinary dosages will correspond to human dosages with amounts administered being in proportion to the weight of the animal as compared to adult humans.

The active ingredient is compounded with a suitable pharmaceutical diluent in unit dosage form. For convenient and effective administration in a preferred embodiment of this invention, a unit dosage form containing the active ingredient in an amount of from about 25 mg. to about 500 mg. is administered. The dosage of compositions containing the active ingredient and one or more other active ingredients is to be determined with reference to the usual dosage of each such ingredient.

The following compositions are illustrative of the compositions of the present invention:

(1) Tablets 10,000 scored tablets for oral use, each containing 500 mg. of 3 (l-methyl-Z-pyrrolidinyl)indole free base, are prepared from the following ingredients:

Grams 3-(l-methyl-Z-pyrrolidinyl)indole free base 5000 Starch, U.S.P. 350 Talc, U.S.P. 250 Calcium stearate 35 

1. A 3-(1-ACYL-2-PYRROLIDINYL)INDOLE OF THE FORMULA:
 13. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA; 